Urea substituted imidazoquinoline ethers

ABSTRACT

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and urea functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

[0001] This application is a continuation-in-part of U.S. Serial No.10/013,060, filed Dec. 6, 2001, which claims the benefit of previouslyfiled Provisional Application Serial No. 60/254,218, filed Dec. 8, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to imidazoquinoline compounds that haveether and urea functionality at the 1-position, and to pharmaceuticalcompositions containing such compounds. The invention also providesmethods of making the compounds and intermediates useful in theirsynthesis. A further aspect of this invention relates to the use ofthese compounds as immunomodulators, for inducing cytokine biosynthesisin animals, and in the treatment of diseases, including viral andneoplastic diseases.

BACKGROUND OF THE INVENTION

[0003] The first reliable report on the 1H-imidazo[4,5-c]quinoline ringsystem, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c] quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

[0004] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and2-substituted derivatives thereof were later found to be useful asantiviral agents, bronchodilators and immunomodulators. These aredescribed in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348;4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of whichare incorporated herein by reference.

[0005] There continues to be interest in the imidazoquinoline ringsystem.

[0006] Certain 1H-imidazo[4,5-c] naphthyridine-4-amines,1H-imidazo[4,5-c] pyridin-4-amines, and 1H-imidazo[4,5-c]quinolin-4-amines having an ether containing substituent at the 1position are known. These are described in U.S. Pat. Nos. 5,268,376;5,389,640; 5,494,916; and WO 99/29693.

[0007] There is a continuing need for compounds that have the ability tomodulate the immune response, by induction of cytokine biosynthesis orother mechanisms.

SUMMARY OF THE INVENTION

[0008] We have found a new class of compounds that are useful ininducing cytokine biosynthesis in animals. Accordingly, this inventionprovides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-aminecompounds that have an ether and urea containing substituent at the1-position. The compounds are defined by Formulas (I) and (II), whichare defined in more detail infra. These compounds share the generalstructural formula:

[0009] wherein X, R₁, R₂, and R are as defined herein for each class ofcompounds having Formulas (I) and (II).

[0010] The compounds of Formulas (I) and (II) are useful as immuneresponse modifiers due to their ability to induce cytokine biosynthesisand otherwise modulate the immune response when administered to animals.This makes the compounds useful in the treatment of a variety ofconditions such as viral diseases and tumors that are responsive to suchchanges in the immune response.

[0011] The invention further provides pharmaceutical compositionscontaining the immune response modifying compounds, and methods ofinducing cytokine biosynthesis in an animal, treating a viral infectionin an animal, and/or treating a neoplastic disease in an animal byadministering a compound of Formula (I) or (II) to the animal.

[0012] In addition, the invention provides methods of synthesizing thecompounds of the invention and novel intermediates useful in thesynthesis of these compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0013] As mentioned earlier, we have found certain compounds that inducecytokine biosynthesis and modify the immune response in animals. Suchcompounds are represented by Formulas (I) and (II), as shown below.

[0014] Imidazoquinoline compounds of the invention, which have ether andurea functionality at the 1-position are represented by Formula (I):

[0015] wherein:

[0016] X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-;

[0017] R₁ is selected from the group consisting of:

[0018] R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl;

[0019] R₄—NR₈—CR₃—NR₅-Z-R₆-alkenyl;

[0020] R₄—NR₈—CR₃—NR₅-Z-R₆-aryl;

[0021] R₄—NR₈—CR₃—NR₅-Z-R₆-heteroaryl;

[0022] R₄—NR₈—CR₃—NR₅-Z-R₆-heterocyclyl;

[0023] R₄—NR₈—CR₃—NR₅R₇;

[0024] R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl;

[0025] R₄—NR₈—CR₃—NR₉-Z-R₆-alkenyl;

[0026] R₄—NR₈—CR₃—NR₉-Z-R₆-aryl;

[0027] R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; and

[0028] R₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl;

[0029] R₂ is selected from the group consisting of:

[0030] hydrogen;

[0031] alkyl;

[0032] alkenyl;

[0033] aryl;

[0034] heteroaryl;

[0035] heterocyclyl;

[0036] alkyl-Y-alkyl;

[0037] alkyl-Y-alkenyl;

[0038] alkyl-Y-aryl; and

[0039] alkyl or alkenyl substituted by one or more substituents selectedfrom the group consisting of:

[0040] OH;

[0041] halogen;

[0042] N(R₅)₂;

[0043] CO—N(R₅)₂;

[0044] CO—C₁₋₁₀ alkyl;

[0045] CO—O—C₁₋₁₀ alkyl;

[0046] N₃;

[0047] aryl;

[0048] heteroaryl;

[0049] heterocyclyl;

[0050] CO-aryl; and

[0051] CO-heteroaryl;

[0052] R₃ is ═O or ═S;

[0053] R₄ is alkyl or alkenyl, which may be interrupted by one or more—O— groups;

[0054] each R₅ is independently H or C₁₋₁₀ alkyl;

[0055] R₆ is a bond, alkyl, or alkenyl, which may be interrupted by oneor more —O— groups;

[0056] R₇ is H or C₁₋₁₀ alkyl which may be interrupted by a hetero atom,or R₇ can join with R₅ to form a ring;

[0057] R₈ is H, C₁₋₁₀ alkyl, or arylalkyl; or R₄ and R₈ can jointogether to form a ring;

[0058] R₉ is C₁₋₁₀ alkyl which can join with R₈ to form a ring;

[0059] Y is —O— or —S(O)₀₋₂—;

[0060] Z is a bond, —CO—, or —SO₂—;

[0061] n is 0 to 4; and

[0062] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0063] or a pharmaceutically acceptable salt thereof.

[0064] The invention also includes tetrahydroimidazoquinoline compoundsthat bear an ether and urea containing substituent at the 1-position.Such tetrahydroimidazoquinoline compounds are represented by Formula(II):

[0065] wherein:

[0066] X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-;

[0067] R₁ is selected from the group consisting of:

[0068] R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl;

[0069] R₄—NR₈—CR₃—NR₅-Z-R₆-alkenyl;

[0070] R₄—NR₈—CR₃—NR₅-Z-R₆-aryl;

[0071] R₄—NR₈—CR₃—NR₅-Z-R₆-heteroaryl;

[0072] R₄—NR₈—CR₃—NR₅-Z-R₆-heterocyclyl;

[0073] R₄—NR₈—CR₃—NR₅R₇;

[0074] R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl;

[0075] R₄—NR₈—CR₃—NR₉-Z-R₆-alkenyl;

[0076] R₄—NR₈—CR₃—NR₉-Z-R₆-aryl;

[0077] R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; and

[0078] R₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl;

[0079] R₂ is selected from the group consisting of:

[0080] hydrogen;

[0081] alkyl;

[0082] alkenyl;

[0083] aryl;

[0084] heteroaryl;

[0085] heterocyclyl;

[0086] alkyl-Y-alkyl;

[0087] alkyl-Y-alkenyl;

[0088] alkyl-Y-aryl; and

[0089] alkyl or alkenyl substituted by one or more substituents selectedfrom the group consisting of:

[0090] OH;

[0091] halogen;

[0092] N(R₅)₂;

[0093] CO—N(R₅)₂;

[0094] CO—C₁₋₁₀ alkyl;

[0095] CO—O—C₁₋₁₀ alkyl;

[0096] N₃;

[0097] aryl;

[0098] heteroaryl;

[0099] heterocyclyl;

[0100] CO-aryl; and

[0101] CO-heteroaryl;

[0102] R₃ is ═O or ═S;

[0103] R₄ is alkyl or alkenyl, which may be interrupted by one or more—O— groups;

[0104] each R₅ is independently H or C₁₋₁₀ alkyl;

[0105] R₆ is a bond, alkyl, or alkenyl, which may be interrupted by oneor more —O— groups;

[0106] R₇ is H or C₁₋₁₀ alkyl which may be interrupted by a hetero atom,or R₇ can join with R₅ to form a ring;

[0107] R₈ is H, C₁₋₁₀ alkyl, or arylalkyl; or R₄ and R₈ can jointogether to form a ring;

[0108] R₉ is C₁₋₁₀ alkyl which can join together with R₈ to form a ring;

[0109] Y is —O— or —S(O)₀₋₂—;

[0110] Z is a bond, —CO—, or —SO₂—;

[0111] n is 0 to 4; and

[0112] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen, andtrifluoromethyl;

[0113] or a pharmaceutically acceptable salt thereof.

[0114] Preparation of the Compounds

[0115] Compounds of the invention can be prepared according to ReactionScheme I where R, R₂, R₃, R₄, R₅, R₈, X and n are as defined above, BOCis tert-butoxycarbonyl and R₁₁ is -Z-R₆-alkyl, -Z-R₆-alkenyl,-Z-R₆-aryl, -Z-R₆-heteroaryl, -Z-R₆-heterocyclyl or R₁₁ is R₇ where R₆,R₇ and Z are as defined above.

[0116] In step (1) of Reaction Scheme I the amino group of anaminoalcohol of Formula X is protected with a tert-butoxycarbonyl group.A solution of the aminoalcohol in tetrahydrofuran is treated withdi-tert-butyl dicarbonate in the presence of a base such as sodiumhydroxide. Many aminoalcohols of Formula X are commercially available;others can be prepared using known synthetic methods.

[0117] In step (2) of Reaction Scheme I a protected aminoalcohol ofFormula XI is converted to an iodide of Formula XII. Iodine is added toa solution of triphenylphosphine and imidazole in dichloromethane; thena solution of a protected aminoalcohol of Formula XI in dichloromethaneis added. The reaction is carried out at ambient temperature.

[0118] In step (3) of Reaction Scheme I a 1H-imidazo[4,5-c]quinolin-1-ylalcohol of Formula XIII is alkylated with an iodide of Formula XII toprovide a 1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XIV. Thealcohol of Formula XIII is reacted with sodium hydride in a suitablesolvent such as N,N-dimethylformamide to form an alkoxide. The iodide isadded to the alkoxide solution at ambient temperature. After theaddition is complete the reaction is stirred at an elevated temperature(˜100° C.). Many compounds of Formula XIII are known, see for example,Gerster, U.S. Pat. No. 4,689,338; others can readily be prepared usingknown synthetic routes, see for example, Gerster et al., U.S. Pat. No.5,605,899 and Gerster, U.S. Pat. No. 5,175,296.

[0119] In step (4) of Reaction Scheme I a 1H-imidazo[4,5-c]quinolin-1-ylether of Formula XIV is oxidized to provide a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XV using a conventionaloxidizing agent capable of forming N-oxides. Preferably a solution of acompound of Formula XIV in chloroform is oxidized using3-chloroperoxybenzoic acid at ambient temperature.

[0120] In step (5) of Reaction Scheme I a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XV is aminated to providea 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI. Step (5) involves(i) reacting a compound of Formula XV with an acylating agent and then(ii) reacting the product with an aminating agent. Part (i) of step (5)involves reacting an N-oxide of Formula XV with an acylating agent.Suitable acylating agents include alkyl- or arylsulfonyl chlorides(e.g., benezenesulfonyl chloride, methanesulfonyl chloride,p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (5)involves reacting the product of part (i) with an excess of an aminatingagent. Suitable aminating agents include ammonia (e.g., in the form ofammonium hydroxide) and ammonium salts (e.g., ammonium carbonate,ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide ispreferred. The reaction is preferably carried out by dissolving theN-oxide of Formula XV in an inert solvent such as dichloromethane or1,2-dichloroethane with heating if necessary, adding the aminating agentto the solution, and then slowly adding the acylating agent. Optionallythe reaction can be carried out in a sealed pressure vessel at anelevated temperature (85-100° C.).

[0121] In step (6) of Reaction Scheme I the protecting group is removedby hydrolysis under acidic conditions to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII. Preferably thecompound of Formula XVI is treated with hydrochloric acid/ethanol atambient temperature or with gentle heating.

[0122] In step (7) of Reaction Scheme I a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII is converted to a ureaor thiourea of Formula XVIII using conventional synthetic methods. Forexample, a compound of Formula XVII can be reacted with an isocyanate offormula R₁₂—N═C=O where R₁₂ is —R₆-alkyl, —R₆-alkenyl, —R₆-aryl,—R₆-heteroaryl or —R₆-heterocyclyl. The reaction can be carried out byadding a solution of the isocyanate in a suitable solvent such asdichloromethane or 1-methyl-2-pyrrolidinone to a solution of a compoundof Formula XVII at ambient temperature. Alternatively, a compound ofFormula XVII can be reacted with a thioisocyanate of formula R₁₂—N═C═S,an acyl isocyanate of formula R₁₂—C(O)—N═C═O, a sulfonyl isocyanate offormula —R₁₂—S(O₂)—N═C═O or a carbamoyl chloride of formula R₁₃—N—C(O)Clwhere R₁₃ is R₁₂ or R₇. The product or a pharmaceutically acceptablesalt thereof can be isolated using conventional methods.

[0123] Compounds of the invention can be prepared according to ReactionScheme II where R, R₂, R₃, R₄, R₅, R₈, R₁₁, X and n are as defined aboveand BOC is tert-butoxycarbonyl.

[0124] In step (1) of Reaction Scheme II the amino group of anaminoalcohol of Formula XIX is protected with a tert-butoxycarbonylgroup. A solution of the aminoalcohol in tetrahydrofuran is treated withdi-tert-butyl dicarbonate in the presence of a base such as sodiumhydroxide. Many aminoalcohols of Formula XIX are commercially available;others can be prepared using known synthetic methods.

[0125] In step (2) of Reaction Scheme II a protected amino alcohol ofFormula XX is converted to a methanesulfonate of Formula XXI. A solutionof a compound of Formula XX in a suitable solvent such asdichloromethane is treated with methanesulfonyl chloride in the presenceof a base such as triethylamine. The reaction can be carried out at areduced temperature (0° C.).

[0126] In step (3a) of Reaction Scheme II a methanesulfonate of FormulaXXI is converted to an azide of Formula XXII. Sodium azide is added to asolution of a compound of Formula XXI in a suitable solvent such asN,N-dimethylformamide. The reaction can be carried out at an elevatedtemperature (80-100° C.).

[0127] In step (3b) of Reaction Scheme II a compound of Formula XXII isalkylated with a halide of formula Hal-R₈ to provide a compound ofFormula XXIII. In compounds where R₈ is hydrogen this step is omitted.The compound of Formula XXII is reacted with sodium hydride in asuitable solvent such as N,N-dimethylformamide or tetrahydrofuran toform the anion and then combined with the halide. The reaction can becarried out at ambient temperature.

[0128] In step (4) of Reaction Scheme II an azide of Formula XXII orXXIII is reduced to provide an amine of Formula XXIV. Preferably, thereduction is carried out using a conventional heterogeneoushydrogenation catalyst such as palladium on carbon. The reaction canconveniently be carried out on a Parr apparatus in a suitable solventsuch as methanol or isopropanol.

[0129] In step (5) of Reaction Scheme II a 4-chloro-3-nitroquinoline ofFormula XXV is reacted with an amine of Formula XXIV to provide a3-nitroquinoline of Formula XXVI. The reaction can be carried out byadding an amine of Formula XXIV to a solution of a compound of FormulaXXV in a suitable solvent such as dichloromethane in the presence of abase such as triethylamine. Many quinolines of Formula XXV are knowncompounds or can be prepared using known synthetic methods, see forexample, Gerster, U.S. Pat. No. 4,689,338 and references cited therein.

[0130] In step (6) of Reaction Scheme II a 3-nitroquinoline of FormulaXXVI is reduced to provide a 3-aminoquinoline of Formula XXVII.Preferably, the reduction is carried out using a conventionalheterogeneous hydrogenation catalyst such as platinum on carbon. Thereaction can conveniently be carried out on a Parr apparatus in asuitable solvent such as toluene.

[0131] In step (7) of Reaction Scheme II a compound of Formula XXVII isreacted with a carboxylic acid or an equivalent thereof to provide a1H-imidazo[4,5-c]quinoline of Formula XIV. Suitable equivalents tocarboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates.The carboxylic acid or equivalent is selected such that it will providethe desired R₂ substituent in a compound of Formula XIV. For example,triethyl orthoformate will provide a compound where R₂ is hydrogen andtriethyl orthovalerate will provide a compound where R₂ is butyl. Thereaction can be run in the absence of solvent or in an inert solventsuch as toluene. The reaction is run with sufficient heating to driveoff any alcohol or water formed as a byproduct of the reaction.Optionally a catalytic amount of pyridine hydrochloride can be included.

[0132] Alternatively, step (7) can be carried out by (i) reacting acompound of Formula XXVII with an acyl halide of formula R₂C(O)Cl andthen (ii) cyclizing. In part (i) the acyl halide is added to a solutionof a compound of Formula XXVII in an inert solvent such as acetonitrileor dichloromethane. The reaction can be carried out at ambienttemperature or at a reduced temperature. In part (ii) the product ofpart (i) is heated in an alcoholic solvent in the presence of a base.Preferably the product of part (i) is refluxed in ethanol in thepresence of an excess of triethylamine or heated with methanolicammonia.

[0133] Steps (8), (9), (10) and (11) are carried out in the same manneras steps (4), (5), (6) and (7) of Reaction Scheme I.

[0134] Compounds of the invention can be prepared according to ReactionScheme III where R, R₂, R₃, R₄, R₅, R₈, R₁₁, X and n are as definedabove.

[0135] In step (1) of Reaction Scheme III a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII is reduced to providea 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of FormulaXXVIII. Preferably the reduction is carried out by suspending ordissolving a compound of Formula XVII in trifluoroacetic acid, adding acatalytic amount of platinum (IV) oxide, and then hydrogenating. Thereaction can be conveniently carried out in a Parr apparatus.

[0136] Step (2) is carried out in the same manner as step (7) ofReaction Scheme I to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXIX.The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0137] Compounds of the invention can also be prepared according toReaction Scheme IV where R, R₁, R₂, X and n are as defined above.

[0138] In step (1) of Reaction Scheme 1V a 4-chloro-3-nitroquinoline ofFormula XXV is reacted with an amine of formula R₁—O—X—NH₂ to provide a3-nitroquinolin-4-amine of Formula XXX. The reaction can be carried outby adding the amine to a solution of a compound of Formula XXV in asuitable solvent such as chloroform or dichloromethane and optionallyheating. Many quinolines of Formula XXV are known compounds, see forexample, Gerster, U.S. Pat. No. 4,689,338 and references cited therein.

[0139] In step (2) of Reaction Scheme IV a 3-nitroquinolin-4-amine ofFormula XXX is reduced using the method of step (6) of Reaction SchemeII to provide a quinoline-3,4-diamine of Formula XXXI.

[0140] In step (3) of Reaction Scheme IV a quinoline-3,4-diamine ofFormula XXXI is cyclized using the method of step (7) of Reaction SchemeII to provide a 1H-imidazo[4,5-c]quinoline of Formula XXXII.

[0141] In step (4) of Reaction Scheme IV a 1H-imidazo[4,5-c]quinoline ofFormula XXXII is oxidized using the method of step (4) of ReactionScheme I to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide of FormulaXXXIII.

[0142] In step (5) of Reaction Scheme IV a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXXIII is aminated usingthe method of step (5) of Reaction Scheme I to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula I. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0143] Compounds of the invention can be prepared according to ReactionScheme V where R, R₂, R₃, R₄, R₅, R₈, R₁₁, X and n are as defined above.

[0144] In step (1) of Reaction Scheme V the BOC group is removed from acompound of Formula XIV using the method of step (6) of Reaction SchemeI to provide a 1H-imidazo[4,5-c]quinoline of Formula XXXIV.

[0145] In step (2) of Reaction Scheme V a 1H-imidazo[4,5-c]quinoline ofFormula XXXIV is converted to a urea or thiourea of Formula XXXV usingthe method of step (7) of Reaction Scheme I.

[0146] In step (3) of Reaction Scheme V a 1H-imidazo[4,5-c]quinoline ofFormula XXXV is oxidized using the method of step (4) of Reaction SchemeI to provide a 1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXXVI.

[0147] In step (4) of Reaction Scheme V a1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXXVI is aminated usingthe method of step (5) of Reaction Scheme I to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XVIII. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0148] The invention also provides novel compounds useful asintermediates in the synthesis of the compounds of Formulas (I) and(II). These intermediate compounds have the structural Formulas (III)and (IV), described in more detail below.

[0149] One class of intermediate compounds has formula (III):

[0150] wherein:

[0151] X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-;

[0152] R₁ is selected from the group consisting of:

[0153] R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl;

[0154] R₄—NR₈-CR₃—NR₅-Z-R₆-alkenyl;

[0155] R₄—NR₈—CR₃—NR₅-Z-R₆-aryl;

[0156] R₄—NR₈—CR₃—NR₅-Z-R₆-heteroaryl;

[0157] R₄—NR₈—CR₃—NR₅-Z-R₆-heterocyclyl; and

[0158] R₄—NR₈—CR₃—NR₅R₇;

[0159] R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl;

[0160] R₄—NR₉—CR₃—NR₉-Z-R₆-alkenyl;

[0161] R₄—NR₈—CR₃—NR₉-Z-R₆-aryl;

[0162] R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; and

[0163] R₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl;

[0164] R₂ is selected from the group consisting of:

[0165] hydrogen;

[0166] alkyl;

[0167] alkenyl;

[0168] aryl;

[0169] heteroaryl;

[0170] heterocyclyl;

[0171] alkyl-Y-alkyl;

[0172] alkyl-Y-alkenyl;

[0173] alkyl-Y-aryl; and

[0174] alkyl or alkenyl substituted by one or more substituents selectedfrom the group consisting of:

[0175] OH;

[0176] halogen;

[0177] N(R₅)₂;

[0178] CO—N(R₅)₂;

[0179] CO—C₁₋₁₀ alkyl;

[0180] CO—O—C₁₋₁₀ alkyl;

[0181] N₃;

[0182] aryl;

[0183] heteroaryl;

[0184] heterocyclyl;

[0185] CO-aryl; and

[0186] CO-heteroaryl;

[0187] R₃ is ═O or ═S;

[0188] R₄ is alkyl or alkenyl, which may be interrupted by one or more—O— groups;

[0189] each R₅ is independently H or C₁₋₁₀ alkyl;

[0190] R₆ is a bond, or is alkyl, or alkenyl, which may be interruptedby one or more —O— groups;

[0191] R₇ is H or C₁₋₁₀ alkyl which may be interrupted by a hetero atom,or R₇ can join with R₅ to form a ring;

[0192] R₈ is H, C₁₋₁₀ alkyl, or arylalkyl; or R₄ and R₈ can join to forma ring;

[0193] R₉ is C₁₋₁₀ alkyl which can join together with R₈ to form a ring;

[0194] Y is —O— or —S(O)₀₋₂—;

[0195] Z is a bond, —CO—, or —SO₂—;

[0196] n is 0 to 4; and

[0197] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0198] or a pharmaceutically acceptable salt thereof.

[0199] Another class of intermediate compounds are theimidazoquinoline-N-oxide compounds of Formula (IV):

[0200] wherein

[0201] X is —CHR₅—, —CHR₅-alkylene-, or —CHR₅-alkenylene-;

[0202] R₁ is selected from the group consisting of:

[0203] R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl;

[0204] R₄—NR₈—CR₃—NR₅-Z-R₆-alkenyl;

[0205] R₄˜NR₉—CR₃—NR₅-Z-R₆-aryl;

[0206] R₄—NR₈—CR₃—NR₅-Z-R₆-heteroaryl;

[0207] R₄—NR₈—CR₃—NR₅-Z-R₆-heterocyclyl;

[0208] R₄—NR₈—CR₃—NR₅R₇;

[0209] R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl;

[0210] R₄—NR₈—CR₃—NR₉-Z-R₆-alkenyl;

[0211] R₄—NR₈—CR₃—NR₉-Z-R₆-aryl;

[0212] R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; and

[0213] R₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl;

[0214] Z is a bond, —CO—, or —SO₂—;

[0215] R₃ is ═O or ═S;

[0216] R₄ is alkyl or alkenyl, which may be interrupted by one or more—O— groups;

[0217] each R₅ is independently H or C₁₋₁₀ alkyl;

[0218] R₆ is a bond, or is alkyl, or alkenyl, which may be interruptedby one or more —O— groups;

[0219] R₇ is H or C₁₋₁₀ alkyl which may be interrupted by a hetero atom,or R₇ can join with R₅ to form a ring;

[0220] R₈ is H, C₁₋₁₀ alkyl, or arylalkyl; or R₄ and R₈ can join to forma ring;

[0221] R₉ is C₁₋₁₀ alkyl which can join together with R₈ to form a ring;

[0222] n is 0 to 4; and

[0223] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl;

[0224] or a pharmaceutically acceptable salt thereof.

[0225] As used herein, the terms “alkyl”, “alkenyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwisespecified, these groups contain from 1 to 20 carbon atoms, with alkenylgroups containing from 2 to 20 carbon atoms. Preferred groups have atotal of up to 10 carbon atoms. Cyclic groups can be monocyclic orpolycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplarycyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl,cyclohexyl and adamantyl.

[0226] In addition, the alkyl and alkenyl portions of —X— groups can beunsubstituted or substituted by one or more substituents, whichsubstituents are selected from the groups consisting of alkyl, alkenyl,aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl.

[0227] The term “haloalkyl” is inclusive of groups that are substitutedby one or more halogen atoms, including perfluorinated groups. This isalso true of groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

[0228] The term “aryl” as used herein includes carbocyclic aromaticrings or ring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl,tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl,benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl,quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl,purinyl, quinazolinyl, and so on.

[0229] “Heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring hetero atom (e.g., O, S, N) and includes allof the fully saturated and partially unsaturated derivatives of theabove mentioned heteroaryl groups. Exemplary heterocyclic groups includepyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl,isothiazolidinyl, and the like.

[0230] The aryl, heteroaryl, and heterocyclyl groups can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, alkylthio,haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto,cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy,arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio,heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino,heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl,alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy,arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino,arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino,heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino,arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino,heteroarylalkylsulfonylamino, alkylaminocarbonylamino,alkenylaminocarbonylamino, arylaminocarbonylamino,arylalkylaminocarbonylamino, heteroarylaminocarbonylamino,heteroarylalkylaminocarbonylamino and, in the case of heterocyclyl, oxo.If any other groups are identified as being “substituted” or “optionallysubstituted”, then those groups can also be substituted by one or moreof the above enumerated substituents.

[0231] Certain substituents are generally preferred. For example,preferred R₁ groups include —R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl and—R₄—NR₈—CR₃—NR₅-Z-R₆-aryl, wherein the alkyl and aryl groups can beunsubstituted or substituted; and R₄ is preferably ethylene orn-butylene or R₄ and R₈ join to form a ring. Preferably no Rsubstituents are present (i.e., n is 0). Preferred R₂ groups includehydrogen, alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and cyclopropylmethyl),methoxyethyl and ethoxymethyl. For substituted groups such assubstituted alkyl or substituted aryl groups, preferred substituentsinclude halogen, nitrile, methoxy, methylthio, trifluoromethyl, andtrifluoromethoxy. One or more of these preferred substituents, ifpresent, can be present in the compounds of the invention in anycombination.

[0232] The invention is inclusive of the compounds described herein inany of their pharmaceutically acceptable forms, including isomers (e.g.,diastereomers and enantiomers), salts, solvates, polymorphs, and thelike. In particular, if a compound is optically active, the inventionspecifically includes each of the compound's enantiomers as well asracemic mixtures of the enantiomers.

[0233] Pharmaceutical Compositions and Biological Activity

[0234] Pharmaceutical compositions of the invention contain atherapeutically effective amount of a compound of the invention asdescribed above in combination with a pharmaceutically acceptablecarrier.

[0235] The term “a therapeutically effective amount” means an amount ofthe compound sufficient to induce a therapeutic effect, such as cytokineinduction, antitumor activity, and/or antiviral activity. Although theexact amount of active compound used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound, thenature of the carrier, and the intended dosing regimen, it isanticipated that the compositions of the invention will containsufficient active ingredient to provide a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of thecompound to the subject. Any of the conventional dosage forms may beused, such as tablets, lozenges, parenteral formulations, syrups,creams, ointments, aerosol formulations, transdermal patches,transmucosal patches and the like.

[0236] The compounds of the invention can be administered as the singletherapeutic agent in the treatment regimen, or the compounds of theinvention may be administered in combination with one another or withother active agents, including additional immune response modifiers,antivirals, antibiotics, etc.

[0237] The compounds of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe tests set forth below. These results indicate that the compounds areuseful as immune response modifiers that can modulate the immuneresponse in a number of different ways, rendering them useful in thetreatment of a variety of disorders.

[0238] Cytokines whose production may be induced by the administrationof compounds according to the invention generally include interferon-α(IFN-α and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 andIL-12, and a variety of other cytokines. Among other effects, these andother cytokines can inhibit virus production and tumor cell growth,making the compounds useful in the treatment of viral diseases andtumors. Accordingly, the invention provides a method of inducingcytokine biosynthesis in an animal comprising administering an effectiveamount of a compound or composition of the invention to the animal.

[0239] Certain compounds of the invention have been found topreferentially induce the expression of IFN-α in a population ofhematopoietic cells such as PBMCs (peripheral blood mononuclear cells)containing pDC2 cells (precursor dendritic cell-type 2) withoutconcomitant production of significant levels of inflammatory cytokines.

[0240] In addition to the ability to induce the production of cytokines,the compounds of the invention affect other aspects of the innate immuneresponse. For example, natural killer cell activity may be stimulated,an effect that may be due to cytokine induction. The compounds may alsoactivate macrophages, which in turn stimulates secretion of nitric oxideand the production of additional cytokines. Further, the compounds maycause proliferation and differentiation of B-lymphocytes.

[0241] Compounds of the invention also have an effect on the acquiredimmune response. For example, although there is not believed to be anydirect effect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the T helper type 2 (Th2) cytokinesIL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.This activity means that the compounds are useful in the treatment ofdiseases where upregulation of the Th1 response and/or downregulation ofthe Th2 response is desired. In view of the ability of compounds of theinvention to inhibit the Th2 immune response, the compounds are expectedto be useful in the treatment of atopic diseases, e.g., atopicdermatitis, asthma, allergy, allergic rhinitis; systemic lupuserythematosis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases and chlamydia.

[0242] The immune response modifying effects of the compounds make themuseful in the treatment of a wide variety of conditions. Because oftheir ability to induce the production of cytokines such as IFN-α and/orTNF-α, the compounds are particularly useful in the treatment of viraldiseases and tumors. This immunomodulating activity suggests thatcompounds of the invention are useful in treating diseases such as, butnot limited to, viral diseases including genital warts; common warts;plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I andType II; molluscum contagiosum; variola, particularly variola major;HIV; CMV; VZV; rhinovirus; adenovirus; influenza; and para-influenza;intraepithelial neoplasias such as cervical intraepithelial neoplasia;human papillomavirus (HPV) and associated neoplasias; fungal diseases,e.g. candida, aspergillus, and cryptococcal meningitis; neoplasticdiseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi'ssarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenousleukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneousT-cell lymphoma, and other cancers; parasitic diseases, e.g.pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection, and leishmaniasis; and bacterial infections,e.g., tuberculosis, and mycobacterium avium. Additional diseases orconditions that can be treated using the compounds of the inventioninclude actinic keratosis; eczema; eosinophilia; essentialthrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome; discoidlupus; Bowen's disease; Bowenoid papulosis; alopecia areata; theinhibition of Keloid formation after surgery and other types ofpost-surgical scars. In addition, these compounds could enhance orstimulate the healing of wounds, including chronic wounds. The compoundsmay be useful for treating the opportunistic infections and tumors thatoccur after suppression of cell mediated immunity in, for example,transplant patients, cancer patients and HIV patients.

[0243] An amount of a compound effective to induce cytokine biosynthesisis an amount sufficient to cause one or more cell types, such asmonocytes, macrophages, dendritic cells and B-cells to produce an amountof one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12 that is increased over the background level of suchcytokines. The precise amount will vary according to factors known inthe art but is expected to be a dose of about 100 ng/kg to about 50mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention alsoprovides a method of treating a viral infection in an animal and amethod of treating a neoplastic disease in an animal comprisingadministering an effective amount of a compound or composition of theinvention to the animal. An amount effective to treat or inhibit a viralinfection is an amount that will cause a reduction in one or more of themanifestations of viral infection, such as viral lesions, viral load,rate of virus production, and mortality as compared to untreated controlanimals. The precise amount will vary according to factors known in theart but is expected to be a dose of about 10 ng/kg to about 50 mg/kg,preferably about 10 μg/kg to about 5 mg/kg. An amount of a compoundeffective to treat a neoplastic condition is an amount that will cause areduction in tumor size or in the number of tumor foci. Again, theprecise amount will vary according to factors known in the art but isexpected to be a dose of about 100 ng/kg to about 50 mg/kg, preferablyabout 10 μg/kg to about 5 mg/kg.

[0244] The invention is further described by the following examples,which are provided for illustration only and are not intended to belimiting in any way.

[0245] In the examples below some of the compounds were purified usingsemi-preparative HPLC. A Waters Fraction Lynx automated purificationsystem was used. The semi-prep HPLC fractions were analyzed using aMicromass LC-TOFMS and the appropriate fractions were combined andcentrifuge evaporated to provide the trifluoroacetate salt of thedesired compound. The structures were confirmed by ¹H NMR.

[0246] Column: Phenomenex Luna C18(2), 10×50 mm, 5 micron particle size,100 Å pore; flow rate: 25 mL/min.; gradient elution from 5-65%B in 4min., then 65 to 95%B in 0.1 min, then hold at 95%B for 0.4 min., whereA=0.05% trifluoroacetic acid/water and B=0.05% trifluoroaceticacid/acetonitrile; fraction collection by mass-selective triggering.

EXAMPLE 1N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea

[0247]

[0248] Part A

[0249] A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol) in 180mL of tetrahydrofuran (THF), under N₂, was cooled to 0° C. and treatedwith 140 mL of 2N NaOH solution. A solution of di-tert-butyl dicarbonate(60.2 g, 0.276 mol) in 180 mL of THF was then added dropwise over 1 h tothe rapidly stirred solution. The reaction mixture was then allowed towarm to room temperature and was stirred an additional 18 h. The THF wasthen removed under reduced pressure and the remaining aqueous slurry wasbrought to pH 3 by addition of 150 mL of 1M H₂SO₄ solution. This wasthen extracted with ethyl acetate (300 mL, 100 mL) and the combinedorganic layers were washed with H₂O (2×) and brine. The organic portionwas dried over Na₂SO₄ and concentrated to give tert-butyl2-(2-hydroxyethoxy)ethylcarbamate as a colorless oil (47.1 g).

[0250] Part B

[0251] A rapidly stirred solution of tert-butyl2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L ofanhydrous CH₂Cl₂ was cooled to 0° C. under N₂ and treated withtriethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL,0.253 mol) was then added dropwise over 30 min. The reaction mixture wasthen allowed to warm to room temperature and was stirred an additional22 h. The reaction was quenched by addition of 500 mL saturated NaHCO₃solution and the organic layer was separated. The organic phase was thenwashed with H₂O (3×500 mL) and brine. The organic portion was dried overNa₂SO₄ and concentrated to give2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as abrown oil (63.5 g).

[0252] Part C

[0253] A stirred solution of2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (63.5 g,0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated withNaN₃ (16.1 g, 0.247 mol) and the reaction mixture was heated to 90° C.under N₂. After 5 h, the solution was cooled to room temperature andtreated with 500 mL of cold H₂O. The reaction mixture was then extractedwith Et₂O (3×300 mL). The combined organic extracts were washed with H₂O(4×100 mL) and brine (2×100 mL). The organic portion was dried overMgSO₄ and concentrated to give 52.0 g of tert-butyl2-(2-azidoethoxy)ethylcarbamate as a light brown oil.

[0254] Part D

[0255] A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g,0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shakenunder H2 (3 Kg/cm²) for 24 h. The solution was then filtered through aCelite pad and concentrated to give 35.3 g of crude tert-butyl2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was usedwithout further purification.

[0256] Part E

[0257] A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151mol) in 500 mL of anhydrous CH₂Cl₂, under N₂, was treated withtriethylamine (43 mL, 0.308 mol) and tert-butyl2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight,the reaction mixture was washed with H₂O (2×300 mL) and brine (300 mL).The organic portion was dried over Na₂SO₄ and concentrated to give abright yellow solid. Recrystallization from ethyl acetate/hexanes gave43.6 g of tert-butyl2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellowcrystals.

[0258] Part F

[0259] A solution of tert-butyl2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shakenunder H2 (3 Kg/cm²) for 24 h. The solution was then filtered through aCelite pad and concentrated to give 6.92 g of crude tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate as a yellowsyrup.

[0260] Part G

[0261] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5mmol) in 250 mL of anhydrous CH₂Cl₂ was cooled to 0° C. and treated withtriethylamine (4.18 mL, 30.0 mmol). Methoxypropionyl chloride (3.30 mL,30.3 mmol) was then added dropwise over 5 min. The reaction was thenwarmed to room temperature and stirring was continued for 1 h. Thereaction mixture was then concentrated under reduced pressure to give anorange solid. This was dissolved in 250 mL of EtOH and 12.5 mL oftriethylamine was added. The mixture was heated to reflux and stirredunder N₂ overnight. The reaction was then concentrated to dryness underreduced pressure and treated with 300 mL of Et₂O. The mixture was thenfiltered and the filtrate was concentrated under reduced pressure togive a brown solid. The solid was dissolved in 200 mL of hot MeOH andtreated with activated charcoal. The hot solution was filtered andconcentrated to give 11.1 g of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamateas a yellow syrup.

[0262] Part H

[0263] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(10.22 g, 24.7 mmol) in 250 mL of CHCl₃ was treated with3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). Afterstirring 30 min, the reaction mixture was washed with 1% Na₂CO₃ solution(2×75 mL) and brine. The organic layer was then dried over Na₂SO₄ andconcentrated to give 10.6 g of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as an orange foam that was used without furtherpurification.

[0264] Part I

[0265] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60° C.and treated with 10 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (7.05 g,37.0 mmol) over a 10 min period. The reaction mixture was treated withan additional 1 mL concentrated NH₄OH solution and then sealed in apressure vessel and heating was continued for 2 h. The reaction mixturewas then cooled and treated with 100 mL of CHCl₃. The reaction mixturewas then washed with H₂O, 1% Na₂CO₃ solution (2×) and brine. The organicportion was dried over Na₂SO₄ and concentrated to give 10.6 g oftert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamateas a brown foam.

[0266] Part J

[0267] Tert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(10.6 g, 24.6 mmol) was treated with 75 mL of 2M HCl in EtOH and themixture was heated to reflux with stirring. After 1.5 h, the reactionmixture was cooled and filtered to give a gummy solid. The solid waswashed EtOH and Et₂O and dried under vacuum to give the hydrochloridesalt as a light brown solid. The free base was made by dissolving thehydrochloride salt in 50 mL of H₂O and treating with 10% NaOH solution.The aqueous suspension was then concentrated to dryness and the residuewas treated with CHCl₃. The resulting salts were removed by filtrationand the filtrate was concentrated to give 3.82 g of1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder.

[0268] MS 330 (M+H)⁺;

[0269]¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, J=8.1 Hz, 1H); 7.66 (d, J=8.2Hz, 1H); 7.40 (m, 1H); 7.25 (m, 1H); 6.88 (br s, 2H); 4.78 (t, J=5.4 Hz,2H); 3.89 (t, J=4.8 Hz, 2H); 3.84 (t, J=6.9 Hz, 2H); 3.54 (t, J=5.4 Hz,2H); 3.31 (s, 3H); 3.23 (t, J=6.6 Hz, 2H); 2.88 (t, J=5.3 Hz, 2H).

[0270] Part K

[0271]1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. The reaction mixture was then treated withphenyl isocyanate (247 μL, 2.28 mmol) and Et₃N (0.64 mL, 4.56 mmol) andallowed to warm slowly to room temperature. After stirring for 2 h, thereaction mixture was concentrated under reduced pressure to yield ayellow solid. The yellow solid was dissolved in a minimum amount ofCH₂Cl₂ and EtOAc was added until the solution became turbid. The mixturewas placed in a freezer overnight and white crystal formed. The crystalswere isolated by filtration and were dried under vacuum to give 126 mgofN-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea.mp 171.0-174.0° C.;

[0272] MS 449 (M+H)⁺;

[0273]¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (s, 1H); 8.05 (d, J=7.7 Hz, 1H);7.62 (d, J=8.8 Hz, 1H); 7.44-7.18 (m, 3H); 7.27-7.18 (m, 3H); 6.88 (t,J=7.3 Hz, 1H); 6.54 (s, 2H); 6.12 (t, J=5.5 Hz, 2H); 4.76 (t, J=4.8 Hz,2H); 3.88 (t, J=5.3 Hz, 2H); 3.81 (t, J=6.7 Hz, 2H); 3.40 (t, J=6.0 Hz,2H); 3.28 (s, 3H); 3.25-3.14 (m, 4H);

[0274]¹³C (75 MHz, DMSO-d₆) δ 155.5, 152.0, 144.9, 140.8, 132.7, 129.0,126.8, 126.5, 121.5, 121.4, 120.5, 117.9, 115.1, 70.5, 69.4, 58.4, 45.5,27.6;

[0275] Anal. Calcd for C₂₄H₂₈N₆O₃.0.21H₂O: %C, 63.73, %H, 6.33, %N,18.58. Found: %C, 63.33, %H, 6.28, %N, 18.67.

EXAMPLE 2N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea

[0276]

[0277] Part A

[0278]1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid andtreated with PtO₂ (1.0 g). The reaction mixture was shaken under H₂ (3Kg/cm²). After 4 d, an additional 0.5 g of PtO₂ was added andhydrogenation was continued for an additional 3 d. The reaction was thenfiltered through Celite and concentrated under reduced pressure to givea brown oil. The oil was dissolved in 200 mL of H₂O then made basic(pH˜11) by addition of 10% NaOH solution. This was then extracted withCHCl₃ (5×75 mL) and the combined organic layers were dried over Na₂SO₄and concentrated to give 5.17 g of1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a tan solid.

[0279] MS 334 (M+H)⁺;

[0280]¹H NMR (300 MHz, CDCl₃) δ 5.19 (s, 2H); 4.49 (t, J=5.4 Hz, 2H);3.84 (t, J=6.6 Hz, 2H); 3.71 (t, J=5.4 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H);3.51 (s, 3H); 3.15 (t, J=6.6 Hz, 2H); 2.95 (m, 2H); 2.82 (m, 2H); 2.76(t, J=5.1 Hz, 2H); 1.84 (m, 4H), 1.47 (br s,2H).

[0281] Part B

[0282]1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(919 mg, 2.76 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. The reaction mixture was then treated withphenyl isocyanate (300 μL, 2.76 mmol) and Et₃N (0.77 mL, 5.51 mmol) andallowed to warm slowly to room temperature. After stirring overnight,the reaction mixture was then quenched by addition of saturated NaHCO₃solution (30 mL). The organic layer was separated and washed with H₂Oand brine, dried over Na₂SO₄ and concentrated under reduced pressure togive a yellow solid. The solid was triturated with Et₂O (30 mL) and afew drops of MeOH. The solid was isolated by filtration and dried undervacuum to give 460 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylureaas a white powder. m.p. 180-182° C.;

[0283] MS 453 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H); 7.37 (d,J=7.7 Hz, 2H); 7.19 (t,J=8.2 Hz, 2H); 6.86 (t,J=7.7 Hz, 1H); 6.11(t,J=5.5 Hz, 2H); 5.70 (s, 2H); 4.43 (t, J=5.1 Hz, 2H); 3.78-3.69 (m,4H); 3.39 (t, J=5.6 Hz, 2H); 3.25 (s, 3H); 3.19 (m, 2H); 3.10 (t, J=6.8Hz, 2H); 2.91 (m, 2H); 2.64 (m, 2H); 1.72 (m, 4H);

[0284]¹³C (75 MHz, DMSO-d₆) δ 155.5, 151.3, 149.3, 146.3, 140.8, 138.5,129.0, 125.0, 121.4, 118.0, 105.6, 70.6, 70.5, 70.4, 58.4, 44.6, 39.2,32.7, 27.6, 23.8, 23.1, 23.0; Anal. Calcd for C₂₄H₃₂N₆O₃: %C, 63.70, %H,7.13, %N, 18.57. Found: %C, 63.33, %H, 7.16, %N, 18.66.

EXAMPLE 3N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N′-phenylurea

[0285]

[0286] Part A

[0287] Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placedin a round bottom flask and washed with hexanes (3×) under N₂. The driedsodium hydride was treated with 800 mL of anhydrous THF. A solution oftert-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mLof THF was then added to the stirred sodium hydride solution over 40min. After addition was complete, the reaction was stirred an additional20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). Afterstirring overnight, the reaction was quenched with 300 mL of saturatedNaHCO₃ solution. The reaction mixture was then treated with 200 mL ofH₂O and 1 L of Et₂O. The organic phase was separated and washed with H₂Oand brine. The organic portion was then dried over MgSO₄ andconcentrated under reduced pressure to give 41.9 g of tert-butyl2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.

[0288] Part B

[0289] A solution tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate(41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd oncarbon and shaken under H₂ (3 Kg/cm²) for 24 h. The solution was thenfiltered through a Celite pad and concentrated to give 37.2 g of crudetert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellowliquid.

[0290] Part C

[0291] A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155mmol) in 400 mL of anhydrous CH₂Cl₂, under N₂, was treated withtriethylamine (43.1 mL, 310 mmol) and tert-butyl2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). Afterstirring overnight, the reaction mixture was washed with H₂O (2×300 mL)and brine (300 mL). The organic portion was dried over Na₂SO₄ andconcentrated to give a brown oil. Column chromatography (SiO₂, 33% ethylacetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butylmethyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as ayellow solid.

[0292] Part D

[0293] A solution of tert-butylmethyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate (6.56 g,16.8 mmol) in 75 mL of toluene was treated with 0.5 g of 5% Pt on carbonand shaken under H2 (3 Kg/cm²) for 24 h. The solution was then filteredthrough a Celite pad and concentrated to give 6.8 g of crude tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate as anorange syrup which was carried on without further purification.

[0294] Part E

[0295] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate (6.05 g,16.8 mmol) in 200 mL of anhydrous CH₂Cl₂ was cooled to 0° C. and treatedwith triethylamine (2.40 mL, 17.2 mmol). Methoxypropionyl chloride (1.72mL, 17.2 mmol) was then added dropwise over 5 min. The reaction was thenwarmed to room temperature and stirring was continued for 3 h. Thereaction mixture was then concentrated under reduced pressure to give anorange solid. This was dissolved in 200 mL of EtOH and 7.2 mL oftriethylamine was added. The mixture was heated to reflux and stirredunder N₂ overnight. The reaction was then concentrated to dryness underreduced pressure and treated with 300 mL of Et₂O. The mixture was thenfiltered and the filtrate was concentrated under reduced pressure togive a brown solid. This was dissolved in 300 mL of CH₂Cl₂ and washedwith H₂O and brine. The organic portion was dried over Na₂SO₄ andconcentrated under reduced pressure to give a brown oil. The oil wasdissolved in 100 mL of hot MeOH and treated with activated charcoal. Thehot solution was filtered and concentrated to give 7.20 g of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamateas a yellow syrup.

[0296] Part F

[0297] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate(7.20 g, 16.8 mmol) in 200 mL of CH₂Cl₂ was treated with MCPBA (77%,4.32 g, 19.3 mmol). After stirring 6 h, the reaction mixture was treatedwith saturated NaHCO₃ solution and the layers were separated. Theorganic portion was washed with H₂O and brine then dried over Na₂SO₄ andconcentrated to give 7.05 g of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamateas a light brown solid.

[0298] Part G

[0299] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate(7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C.and treated with 5 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (3.33 g,17.5 mmol) over a 10 min period. The reaction mixture was treated withan additional 5 mL concentrated NH₄OH solution and then sealed in apressure vessel and heating was continued for 4 h. The reaction mixturewas then cooled and treated with 100 mL of CH₂Cl₂. The reaction mixturewas then washed with H₂O, 1% Na₂CO₃ solution (3×) and brine. The organicportion was dried over Na₂SO₄ and concentrated to give 6.50 g oftert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamateas a brown oil.

[0300] Part H

[0301] Tert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate(6.50 g, 14.7 mmol) was dissolved in 100 mL of EtOH and treated with 20mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring.After 6 h, the reaction mixture was cooled and filtered to give a gummysolid. The solid was washed with EtOH and Et₂O and dried under vacuum togive the hydrochloride salt as a light brown powder. The free base wasmade by dissolving the hydrochloride salt in 50 mL of H₂O and treatingwith 5 mL of concentrated NH₄OH. The aqueous suspension was extractedwith CH₂Cl₂ (5×50 mL). The combined organic layers were dried overNa₂SO₄ and concentrated to give 3.93 g of2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder.

[0302] MS 344 (M+H)⁺;

[0303]¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=7.7 Hz, 1H); 7.62 (dd,J=1.0, 8.3 Hz, 1H); 7.42 (ddd, J=1.0, 7.1, 8.2 Hz, 1H); 7.22 (ddd,J=1.1, 7.1, 8.2 Hz, 1H); 6.49 (s, 2H); 4.75 (t, J=5.1 Hz, 2H); 3.83 (t,J=6.8 Hz, 4H); 3.35 (t, J=5.6 Hz, 2H); 3.30 (s, 3H); 3.21 (t, J=6.9 Hz,2H); 2.45 (t, J=5.6 Hz, 2H); 2.12 (s, 3H).

[0304] Part I

[0305]2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine(929 mg, 2.71 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andtreated with phenyl isocyanate (300 μL, 2.76 mmol). After stirring underN₂ overnight, the reaction mixture was concentrated under reducedpressure. Purification by column chromatography (SiO₂, 3% MeOH/CHCl₃saturated with aqueous NH₄OH) gave the product as a white solid.Crystallization from H₂O and MeOH gave 610 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N′-phenylurea as a flakey white crystals. m.p.184.8-185.8° C.;

[0306] MS 463 (M+H)⁺;

[0307]¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (s, 1H); 8.06 (d, J=7.7 Hz, 1H);7.61 (dd, J=1.0, 8.3 Hz, 1H); 7.43-7.38 (m, 3H); 7.25-7.17 (m, 3H); 6.91(t, J=7.3 Hz, 1H); 6.47 (s, 2H); 4.76 (t, J=5.0 Hz, 2H); 3.88 (t, J=5.1Hz, 2H); 3.78 (t, J=6.8 Hz, 2H); 3.48 (t, J=5.2 Hz, 2H); 3.39 (t, J=5.4Hz, 2H); 3.27 (s, 3H); 3.20 (t, J=6.8 Hz, 2H); 2.82 (s, 3H);

[0308]¹³C NMR (75 MHz, DMSO-d₆) δ 155.6, 152.0, 151.9, 145.1, 140.9,132.7, 128.5, 126.7, 126.6, 122.0, 121.4, 120.5, 120.1, 115.1, 70.5,69.6, 69.4, 58.4, 47.7, 45.5, 35.4, 27.6.

[0309] Anal. Calcd for C₂₅H₃₀N₆O₃.0.12H₂O: %C, 64.62; %H, 6.56; %N,18.08. Found: %C, 64.69; %H, 6.65; %N, 18.09.

EXAMPLE 4N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N′-phenylurea

[0310]

[0311] Part A

[0312]2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine(4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid andtreated with PtO₂ (0.5 g). The reaction mixture was shaken under H₂ (3Kg/cm²). After 4 d, an additional 0.5 g of PtO₂ was added andhydrogenation was continued for an additional 3 d. The reaction was thenfiltered through Celite and concentrated under reduced pressure to givea yellow oil. The yellow oil was dissolved in 50 mL of H₂O and extractedwith 50 mL of CHCl₃. The organic portion was removed and discarded. Theaqueous portion was then made basic (pH-12) by addition of 10% NaOHsolution. This was then extracted with CHCl₃ (6×50 mL) and the combinedorganic layers were dried over Na₂SO₄ and concentrated to a brown oil.The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 gof activated charcoal. The hot solution was filtered through Celite andconcentrated to dryness. The resulting gummy solid was concentratedseveral times with Et₂O to give 3.19 g of2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas an off-white powder.

[0313] MS 348 (M+H)⁺;

[0314]¹H NMR (300 MHz, CDCl₃) δ 4.84 (s, 2H); 4.48 (t, J=5.7 Hz, 2H);3.84 (t, J=6.7 Hz, 2H); 3.70 (t, J=5.7 Hz, 2H); 3.46 (t, J=5.1 Hz, 2H);3.36 (s, 3H); 3.14 (t, J=6.7 Hz, 2H); 2.96 (m, 2H); 2.83 (m, 2H); 2.65(t, J=5.1 Hz, 2H); 2.36 (s, 3H); 1.85 (m, 4H).

[0315] Part B

[0316]2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-4-amine(750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andtreated with phenyl isocyanate (239 μL, 2.20 mmol). After stirring underN₂ overnight, the reaction mixture was concentrated under reducedpressure. Crystallization from EtOAc and CH₂Cl₂ gave 170 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N′-phenylurea as fluffy white crystals. m.p.167.7-170.0° C.;

[0317] MS 467 (M+H)⁺;

[0318]¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H); 7.43 (d, J=7.6 Hz, 2H);7.21 (t, J=7.9 Hz, 2H); 6.91 (t, J=7.3 Hz, 1H); 5.65 (s, 2H); 4.43 (t,J=5.0 Hz, 2H); 3.72 (t, J=7.0 Hz, 2H); 3.70 (t, J=5.2 Hz, 2H); 3.46-3.41(m, 4H); 3.24 (s, 3H); 3.07 (t, J=6.9 Hz, 2H); 2.92 (m, 2H); 2.85 (s,3H); 2.64 (m, 2H); 1.72 (m, 4H);

[0319]¹³C NMR (75 MHz, DMSO-d₆) δ 155.6, 151.2, 149.3, 146.3, 140.9,138.4, 128.5, 124.9, 122.0, 120.1, 105.5, 70.7, 70.5, 69.5, 58.4, 48.0,44.6, 35.5, 32.8, 27.6, 23.8, 23.1, 23.0.

[0320] Anal. Calcd for C₂₅H₃₄N₆O₃: %C, 64.36; %H, 7.35; %N, 18.01.Found: %C, 64.04; %H, 7.38; %N, 18.02.

EXAMPLE 5

[0321]N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide

[0322] Under a nitrogen atmosphere,1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.75 g, 2.3 mmol) was dissolved in dichloromethane (30 mL) andtriethylamine (0.64 mL, 4.6 mmol) using mild heat and vigorous stirring.The solution was chilled in an ice-water bath and 4-morpholinecarbonylchloride (0.27 mL, 2.3 mmol) was added dropwise. The cooling bath wasremoved and the reaction was stirred for an additional 4 hours. Thereaction was quenched by the addition of saturated sodium bicarbonatesolution (25 mL). The phases were separated and the organic layer waswashed with water (3×25 ml), brine (25 mL), dried (Na₂SO₄), filtered andconcentrated to yield a yellow foam. The product was recrystallized fromdichloromethane and ethyl acetate. The crystals were triturated withether (2×5 mL) to remove residual solvent. The final product was driedin a vacuum oven to provide 200 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamideas a tan crystalline solid, m.p. 164-166° C.

[0323]¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.3Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.51 (s, 2H),6.33 (t, J=5.0 Hz, 1H), 4.74 (t, J=4.3 Hz, 2H), 3.85-3.81 (m, 4H), 3.49(t, J=4.3 Hz, 4H), 3.33 (t, J=5.9 Hz, 2H), 3.30 (s, 3H), 3.21 (t, J=6.8Hz, 2H), 3.14 (t, J=4.5 Hz, 4H), 3.08 (t, J=6.0 Hz, 2H);

[0324]¹³C NMR (75 MHz, DMSO-d₆) δ 157.8, 151.9, 145.0, 132.7, 126.7,126.6, 121.4, 120.5, 115.1, 70.4, 70.2, 69.2, 58.4, 45.5, 44.0, 27.6;

[0325] Anal. Calcd for C₂₂H₃₀N₆O₄: %C, 59.71, %H, 6.83, %N, 18.99.Found: %C, 59.71, %H, 6.80,% N, 18.78;

[0326] MS(CI) m/e 443 (M+H)

EXAMPLE 6N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmorpholine-4-carboxamide

[0327]

[0328]2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine(802 mg, 2.34 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. To the stirred solution were added Et₃N (0.65mL, 4.68 mmol) and morpholinecarbonyl chloride (273 μL, 2.34 mmol) andthe reaction was allowed to warm to room temperature overnight. Thereaction mixture was then quenched by addition of saturated NaHCO₃solution (30 mL) and CH₂Cl₂ (30 mL). The organic layer was separated andwashed with H₂O and brine, dried over Na₂SO₄ and concentrated underreduced pressure. Purification by column chromatography (SiO₂, 2-5%MeOH/CHCl₃ saturated with aqueous NH₄OH) gave the product as a colorlessfoam. Crystallization from EtOAc gave 640 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmorpholine-4-carboxamideas white crystals. Mp=121.8-122.3° C.

[0329] MS 457 (M+H)⁺;

[0330]¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (dd, J=0.9, 8.3 Hz, 1H); 7.61(dd, J=1.1, 8.3 Hz, 1H); 7.41(ddd, J=1.2, 7.0, 8.3 Hz, 1H); 7.22 (ddd,J=1.3, 7.0, 8.1 Hz, 1H); 6.44 (s, 2H); 4.74 (t, J=5.2 Hz, 2H); 3.84 (t,J=5.2 Hz, 2H); 3.82 (t, J=6.9 Hz, 2H); 3.50-3.43 (m, 6H); 3.30 (s, 3H);3.20 (t, J=6.9 Hz, 2H); 3.16 (t, J=5.5 Hz, 2H); 2.88 (t, J=4.7 Hz, 4H);2.59 (s, 3H);

[0331]¹³C NMR (75 MHz, DMSO-d₆) δ 163.8, 152.0, 151.8, 145.2, 132.7,126.7, 121.3, 120.6, 115.1, 70.4, 69.4, 68.9, 66.1, 58.5, 49.1, 47.3,45.5, 36.9, 27.7.

[0332] Anal. Calcd for C₂₃H₃₂N₆O₄: %C, 60.51; %H, 7.07; %N, 18.41.Found: %C, 60.56; %H, 6.85; %N, 18.19.

EXAMPLES 7-21

[0333] Part A

[0334] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mgportion of pyridinium hydrochloride was then added and refluxing wascontinued for 4 h. The reaction was then concentrated to dryness underreduced pressure. The residue was dissolved in 50 mL of CH₂Cl₂ andwashed with saturated NaHCO₃, H₂O and brine. The organic portion wasdried over Na₂SO₄ and concetrated to give a green oil. The green oil wasdissolved in 50 mL of hot MeOH and treated with activated charcoal. Thehot solution was filtered and concentrated to give 4.12 g of tert-butyl2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as ayellow oil.

[0335] Part B

[0336] A solution of tert-butyl2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12g, 10.0 mmol) in 50 mL of CH₂Cl₂ was treated with 3-chloroperoxybenzoicacid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirring for 5 h, thereaction mixture was treated with saturated NaHCO₃ solution and thelayers were separated. The organic portion was washed with H₂O and brinethen dried over Na₂SO₄ and concentrated to give 3.68 g of tert-butyl2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light brown foam.

[0337] Part C

[0338] A solution of tert-butyl2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C.and treated with 10 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (1.87 g,9.81 mmol) over a 10 min period. The reaction mixture was then sealed ina pressure vessel and heating was continued for 2 h. The reactionmixture was then cooled and treated with 100 mL of CH₂Cl₂. The reactionmixture was then washed with H₂O, 1% Na₂CO₃ solution (3×) and brine. Theorganic portion was dried over Na₂SO₄ and concentrated to give 3.68 g oftert-butyl2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light brown foam.

[0339] Part D

[0340] Tert-butyl2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(3.68 g, 8.60 mmol) was suspended in 20 mL of 2M HCl in EtOH and themixture was heated to reflux with stirring. After 3 h, the reactionmixture was concentrated to give a solid. The solid was triturated withhot EtOH (50 mL) and filtered to give 2.90 g of the product as thehydrochloride salt. The free base was made by dissolving thehydrochloride salt in 50 mL of H₂O and treating with 5 mL ofconcentrated NH₄OH. The aqueous suspension was extracted with CH₂Cl₂(3×50 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to give1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine asa tan powder.

[0341] MS 328 (M+H)⁺;

[0342]¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=8.3 Hz, 1H); 7.83 (d, J=8.4Hz, 1H); 7.50 (m, 1H); 7.30 (m, 1H); 5.41 (s, 2H); 4.69 (t, J=5.6 Hz,2H); 3.93 (t, J=5.6 Hz, 2H); 3.39 (t, J=5.1 Hz, 2H); 2.97 (t, J=7.9 Hz,2H); 2.76 (t, J=5.1 Hz, 2H); 1.89 (m, 2H); 1.52 (m, 2H); 1.26 (br s,2H); 1.01 (t, J=7.3 Hz, 3H).

[0343] Part E

[0344] The compounds in the table below were prepared according to thesynthetic method of step (7) of Reaction Scheme I above using thefollowing general method.

[0345] The isocyanate (84 μmol.) was added to a test tube containing asolution of1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (25mg, 76 μmol) in dichloromethane (5 mL). The test tube was capped andthen placed on a shaker at ambient temperature for 20 hr. The solventwas removed by vacuum centrifugation. The residue was purified bysemi-preparative HPLC using the method described above. The table belowshows the structure of the free base and the observed accurate mass(M+H). Example Accurate Mass Number Structure of Free Base (obs.) 7

413.2644 8

427.2841 9

427.2823 10

447.2496 11

441.2638 12

453.2980 13

472.2457 14

477.2611 15

487.2804 16

490.2919 17

493.2386 18

207.2741 19

511.2120 20

525.2280 21

545.1758

EXAMPLES 22-36

[0346] Part A

[0347] Using the general method of Part A of Examples 7-21, 4-piperidineethanol (10 g, 77.4 mmol) was reacted with di-tert-butyl dicarbonate(17.7 g, 81.3 mmol) to provide 13.1 g of tert-butyl4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear oil.

[0348] Part B

[0349] Iodine (7.97 g) was added in three portions to a solution ofimidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1mmol) in dichloromethane (350 mL). After 5 minutes a solution of thematerial from Part A in dichloromethane (70 mL) was added. The reactionmixture was stirred at ambient temperature overnight. More iodine (7.97g) was added and the reaction was stirred at ambient temperature for 1hr. The reaction mixture was washed with saturated sodium thiosulfate(2×) and brine, dried over sodium sulfate, filtered and thenconcentrated under reduced pressure to provide an oily residue. Theresidue was purified by column chromatography (silica gel eluting with20% ethyl acetate in hexanes) to provide 15.52 g of tert-butyl4-(2-iodoethyl)piperidine-1-carboxylate as a pale yellow oil.

[0350] Part C

[0351] Under a nitrogen atmosphere,2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (6.5 g, 26.9 mmol) wasadded in three portions to a suspension of sodium hydride (1.4 g of 60%,35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction mixture wasallowed to stir for 45 minutes by which time gas evolution had ceased.Tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol)was added dropwise over a period of 15 minutes. The reaction mixture wasallowed to stir at ambient temperature for 2.5 hrs; then it was heatedto 100° C. and stirred overnight. Analysis by HPLC showed that thereaction was about 35% complete. Saturated ammonium chloride solutionwas added, the resulting mixture was allowed to stir for 20 minutes andthen it was extracted with ethyl acetate (2×). The ethyl acetateextracts were washed with water (2×) and then with brine, combined,dried over sodium sulfate, filtered and then concentrated under reducedpressure to provide a brown oil. The oil was purified by columnchromatography (silica gel eluting sequentially with 30% ethyl acetatein hexanes, 50% ethyl acetate in hexanes, and ethyl acetate) to provide2.2 g of tert-butyl4-{2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate.

[0352] Part D

[0353] Using the general method of Examples 7-21 Part H, the materialfrom Part C was oxidized to provide tert-butyl4-{2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylateas an oil.

[0354] Part E

[0355] Ammonium hydroxide solution (20 mL) was added to a solution ofthe material from Part D in dichloromethane (20 mL). A solution of tosylchloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was added over aperiod of 5 minutes. The resulting biphasic reaction mixture was allowedto stir overnight. The reaction mixture was diluted with chloroform andsaturated sodium bicarbonate solution. The layers were separated. Theorganic layer was dried over sodium sulfate, filtered and thenconcentrated under reduced pressure to provide a brown glass. Thismaterial was purified by column chromatography (silica gel eluting firstwith 50% ethyl acetate in hexanes and then with ethyl acetate) toprovide 1.0 g of tert-butyl4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylateas pale yellow glassy foam.

[0356] Part F

[0357] Under a nitrogen atmosphere, tert-butyl4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate(1.00 g, 2.1 mmol) and 2N ethanolic hydrochloric acid (10 ml, 20 mmol)were combined and the solution was stirred at ambient temperature for 14hours. The solvent was removed in vacuo and the resulting tan solid wasdissolved in water. Saturated aqueous sodium carbonate was added untilthe pH reached 10. After extraction with dichloromethane (3×), theorganic fractions were combined, washed with brine, dried (Na₂SO₄),filtered, and the majority of the solvent was removed in vacuo. Hexanewas added to form a precipitate. Vacuum filtration yielded 0.5 g of1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder.

[0358]¹H-NMR (300 MHz, DMSO-d₆): δ 8.34 (bs, 1H), 8.19 (d, J=8.49 Hz,1H), 7.61 (dd, J=8.31, 1.13 Hz, 1H), 7.45-7.39 (m, 1H), 7.25-7.19 (m,1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H), 3.5-3.3 (m,2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H), 2.09-1.99 (m, 2H), 1.8-1.63(bs, 1H), 1.37-1.0 (m, 5H), 0.95-0.7 (m, 5H);

[0359]¹³C-NMR (75 MHz, DMSO-d₆): δ 152.8, 145.8, 140.6, 133.0, 127.8,127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1, 58.4, 46.1, 36.3, 33.1,32.7, 24.5, 9.9;

[0360] MS (CI) m/e 368.2459 (368.2450 calcd for C₂₁H₃₀N₅O).

[0361] Part G

[0362] The compounds in the table below were prepared according to thesynthetic method of step (7) of Reaction Scheme I above using thefollowing general method.

[0363] The isocyanate or isothiocyanate (75 μmol.) was added to a testtube containing a solution of1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine(25 mg, 68 μmol) in dichloromethane (5 mL). The test tube was capped andthen placed on a shaker at ambient temperature for 20 hr. The solventwas removed by vacuum centrifugation. The residue was purified bysemi-preparative HPLC using the method described above. The table belowshows the structure of the free base and the observed accurate mass(M+H). Example Accurate Mass Number Stucture of Free Base (obs.) 22

453.2983 23

467.3138 24

487.2787 25

481.2930 26

493.3270 27

512.2757 28

517.2907 29

527.3112 30

529.2911 31

533.2704 32

547.3032 33

565.2641 34

585.2056 35

521.2297 36

503.2589

EXAMPLES 37-44

[0364] Part A

[0365] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g, 20.0mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mgportion of pyridinium hydrochloride was then added and refluxing wascontinued for 2 h. The reaction was then concentrated to dryness underreduced pressure. The residue was dissolved in 200 mL of CH₂Cl₂ andwashed with saturated NaHCO₃, H₂O and brine. The organic portion wasdried over Na₂SO₄ and concentrated to give a green oil. The green oilwas dissolved in 200 mL of hot MeOH and treated with 10 g of activatedcharcoal. The hot solution was filtered and concentrated to give 5.25 gof tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light yellow syrup.

[0366] Part B

[0367] A solution of tert-butyl2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7mmol) in 200 mL of CH₂Cl₂ was treated with MCPBA (77%, 3.63 g, 16.3mmol). After stirring overnight, the reaction mixture was treated withsaturated NaHCO₃ solution and the layers were separated. The organicportion was washed with H₂O and brine then dried over Na₂SO₄ andconcentrated to give 4.60 g of tert-butyl2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as alight brown foam.

[0368] Part C

[0369] A solution of tert-butyl2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.60g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80° C. andtreated with 10 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (2.71 g,14.2 mmol) over a 10 min period. The reaction mixture was treated withan additional 2 mL of concentrated NH₄OH solution and then sealed in apressure vessel and heating was continued for 3 h. The reaction mixturewas then cooled and treated with 100 mL of CH₂Cl₂. The reaction mixturewas then washed with H₂O, 1% Na₂CO₃ solution (3×) and brine. The organicportion was dried over Na₂SO₄ and concentrated to give 4.56 g oftert-butyl2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as alight brown foam.

[0370] Part D

[0371] Tert-butyl2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.56g, 12.3 mmol) was dissolved in 100 mL of EtOH and treated with 30 mL of2M HCl in EtOH and the mixture was heated to reflux with stirring. After3 h, the reaction mixture was concentrated to give a solid. The solidwas triturated with hot EtOH (100 mL) and filtered to give the productas the hydrochloride salt. The free base was made by dissolving thehydrochloride salt in 50 mL of H₂O and treating with 5 mL ofconcentrated NH₄OH. The aqueous suspension was extracted with CH₂Cl₂(5×50 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to give 1.35 g of1-[2-(2-aminoethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as a tanpowder.

[0372] MS 272 (M+H)⁺;

[0373]¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J=8.2 Hz, 1H); 7.88 (s, 1H);7.84 (d, J=8.4 Hz, 1H); 7.54 (m, 1H); 7.32 (m, 1H); 5.43 (s, 2H); 4.74(t, J=5.2 Hz, 2H); 3.97 (t, J=5.2 Hz, 2H); 3.42 (t, J=5.1 Hz, 2H); 2.78(t, J=5.1 Hz, 2H); 1.10 (br s, 2H).

[0374] Part E

[0375] The compounds in the table below were prepared according to thesynthetic method of step (7) of Reaction Scheme I above using thefollowing general method.

[0376] 1-[2-(2-Aminoethoxy)ethyl]-1H-midazo[4,5-c]quinolin-4-amine (20mg, 74 μmol) and 1-methyl-2-pyrrolidinone (5 mL) were combined in a testtube and then sonicated with heating to provide a solution. Theisocyanate (81 μmol.) was added, the test tube was capped and thenplaced on a shaker at ambient temperature for 20 hr. The solvent wasremoved by vacuum centrifugation. The residue was purified bysemi-preparative HPLC using the method described above. The table belowshows the structure of the free base and the observed accurate mass(M+H). Example Accurate Mass Number Stucture of Free Base (obs.) 37

371.2204 38

391.1884 39

397.2373 40

416.1844 41

421.1946 42

431.2206 43

451.2115 44

455.1513

EXAMPLE 451-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine

[0377]

[0378] Part A

[0379] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (12.05 g, 34.8mmol) in 200 mL of 1,2-dichloroethane was treated with trimethylorthoacetate (5.50 mL, 43.2 mmol) and the reaction mixture was heated toreflux. A 100 mg portion of pyridinium hydrochloride was then added andrefluxing was continued for 4 h. The reaction was then cooled and washedwith water and brine. The organic portion was dried over Na₂SO₄ andconcentrated to give an orange foam. The foam was triturated with etherand filtered to yield 10.76 g of tert-butyl2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as atan solid.

[0380] Part B

[0381] A solution of tert-butyl2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(10.75 g, 29.0 mmol) in 150 mL of CHCl₃ was chilled in an ice waterbath. The solution was treated with 3-chloroperoxybenzoic acid (MCPBA,70%, 10.73 g, 43.5 mmol). After stirring for 1.5 h, the reaction mixturewas washed with 1% Na₂CO₃ (3×) solution and the layers were separated.The organic portion was washed with H₂O and brine then dried over Na₂SO₄and concentrated to give a sticky brown solid. The solid was trituratedwith ether to yield 11.21 g of tert-butyl2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light tan solid.

[0382] Part C

[0383] A solution of tert-butyl2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(11.21 g, 29.0 mmol) in 75 mL of CH₂Cl₂ was treated with 75 mL ofconcentrated NH₄OH solution. The mixture was chilled in an ice waterbath. To the rapidly stirred mixture was added solid p-toluenesulfonylchloride (5.53 g, 29.0 mmol) over a 10 min period. The reaction mixturewas then warmed to room temperature and treated with 75 mL of CH₂Cl₂ and75 mL of water. The organic portion was then washed with 1% Na₂CO₃solution (3×) and brine. The organic portion was dried over Na₂SO₄ andconcentrated and triturated in ether to yield 7.13 g of tert-butyl2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light green solid.

[0384] Part D

[0385] Tert-butyl2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(7.13 g, 18.5 mmol) was suspended in 100 mL of 2M HCl in EtOH and themixture was heated to reflux with stirring. After 3 h, the reactionmixture was chilled in an ice water bath and a filtered. The resultingwas washed with small portions of ether to give the product as thehydrochloride salt. The free base was made by dissolving thehydrochloride salt in 100 mL of H₂O and treating with 20 mL ofconcentrated NH₄OH. The aqueous suspension was extracted with CH₂Cl₂(3×75 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to give 5.10 g of1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amineasa tan powder.

[0386] mp 155-157° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=7.5 Hz,1H), 7.61 (d, J=8.3 Hz, 1H), 7.41 (t, J=7.0 Hz, 1H), 7.22 (t, J=8.1 Hz,1H), 6.50 (s, 2H), 4.70 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H), 3.27(t, J=5.4 Hz, 2H), 3.03 (bs, 2H), 2.61 (s, 3H), 2.53 (t, J=5.6 Hz, 2H);¹³C NMR (75 MHz, DMSO-d₆) δ 152.0, 150.9, 145.1, 132.8, 126.6, 121.3,120.5, 115.1, 73.6, 69.4, 45.8, 41.6, 14.1; MS m/z 286 (M+H)⁺; Anal.Calcd for C₁₅H₁₉N₅O: C, 63.14, H, 6.71, N, 24.54. Found: C, 62.74, H,6.68, N, 24.55.

EXAMPLE 461-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0387]

[0388] Part A

[0389] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (32.0 g, 92.0mmol) in 300 mL of CH₂Cl₂ was treated with triethylamine (19.2 mL, 138.0mmol). The reaction was chilled in an ice water bath and then propionylchloride (9.40 mL, 108.2 mmol) was added dropwise. After stirring for 18h, the reaction was treated with water (150 mL) and the layers wereseparated. The aqueous portion was extracted with CH₂Cl₂ (3×50 mL). Thecombined organic portions were washed with 1% Na₂CO₃, water, brine,dried over Na₂SO₄, filtered and concentrated to yield a red stickysolid. The solid was triturated with ether and filtered to yield 16.5 gof tert-butyl2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamate as anoff white powder.

[0390] Part B

[0391] A solution of tert-butyl2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamate(15.00 g, 37.3 mmol) in 200 mL of EtOH was treated with triethylamine(13.0 mL, 93.2 mmol). The reaction was heated to reflux with stirring.After 3 days, the reaction was concentrated, triturated with ether andfiltered to yield 13.78 g of tert-butyl2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as anoff white solid.

[0392] Part C

[0393] A solution of tert-butyl2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(13.78 g 35.8 mmol) in 175 mL of CHCl₃ was treated with3-chloroperoxybenzoic acid (MCPBA, 70%, 10.28 g, 41.7 mmol). Afterstirring for 3 h, the reaction mixture was treated with water (100 mL)and CHCl₃ (50 mL) and the layers were separated. The organic portion waswashed with 1% Na₂CO₃ solution (2×), water and brine then dried overNa₂SO₄ and concentrated to give 14.35 g tert-butyl2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a sticky tan solid.

[0394] Part D

[0395] A solution of tert-butyl2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(14.3 g, 35.8 mmol) in 90 mL of CH₂Cl₂ was treated with 90 mL ofconcentrated NH₄OH solution. The mixture was chilled in an ice waterbath. To the rapidly stirred mixture was added solid p-toluenesulfonylchloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixturewas then warmed to room temperature. After 30 min, the reaction wastreated with 90 mL of CH₂Cl₂ and 90 mL of water. The organic portion wasthen washed with 1% Na₂CO₃ solution (2×), water, brine, dried overNa₂SO₄ and concentrated. The resulting solid was triturated in ether andfiltered to yield 9.35 g of tert-butyl2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light tan solid.

[0396] Part E

[0397] Tert-butyl2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(9.35 g, 23.4 mmol) was suspended in 150 mL of 2M HCl in EtOH and themixture was heated to reflux with stirring. After 2 h, the reaction wascooled to room temperature and the HCl salt of the product was collectedby vacuum filtration and rinsed with ether. The free base was made bydissolving the HCl salt in water and treating with 10% NaOH solutionuntil the mixture was pH 12. The aqueous suspension was extracted withCH₂Cl₂ (10×50 mL). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated to give 6.62 g of1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine asa light yellow solid.

[0398] mp=144-146° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=7.5 Hz,1H), 7.61 (dd, J=1.0, 8.3 Hz, 1H), 7.43-7.38 (m, 1H), 7.25-7.17 (m, 1H),6.45 (s, 2H), 4.71 (t, J=5.2 Hz, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.27 (t,J=5.7 Hz, 2H), 2.97 (q, J=7.5 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H), 1.37 (t,J=7.5 Hz, 3H), 1.25 (bs, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 155.2, 152.1,145.1, 132.8, 126.6, 126.6, 121.3, 120.5, 115.2, 73.8, 69.4, 45.4, 41.6,20.4, 12.2; MS m/z 300 (M+H)⁺; Anal. Calcd for C₁₆H₂₁N₅O: C, 64.19; H,7.07; N, 23.39; Found: C, 63.98; H, 6.96; N, 23.27.

EXAMPLE 471-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0399]

[0400] Part A

[0401] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (18.04 g, 52.1mmol) in 180 mL of pyridine was treated with 50 mg of4-dimethylaminopyridine and chilled in an ice water bath. 2-ethoxyacetylchloride (6.44 g, 52.6 mmol) was added dropwise to the solution. Thereaction was stirred at room temperature for 3 h. The reaction was thenheated to reflux with stirring. After 18 h the reaction was cooled andthen concentrated. The residue was partitioned between CHCl₃ (150 mL)and water (150 mL) and the layers were separated. The aqueous portionwas extracted with CHCl₃ (3×50 mL). The combined organic portions werewashed with brine, dried over Na₂SO₄, filtered and concentrated to yield15.47 g of tert-butyl2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamateas a sticky yellow solid.

[0402] Part B

[0403] A solution of tert-butyl2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(15.47 g, 37.3 mmol) in 150 mL of CHCl₃ was treated with3-chloroperoxybenzoic acid (MCPBA, 70%, 15.12 g, 61.3 mmol). Afterstirring for 1.5 h, the reaction mixture was treated with water (100 mL)and CHCl₃ (50 mL) and the layers were separated. The organic portion waswashed with 2% Na₂CO₃ solution (2×), H₂O and brine then dried overNa₂SO₄ and concentrated to give 16.06 g of tert-butyl2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamateas a yellow solid.

[0404] Part C

[0405] A solution of tert-butyl2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(16.06 g, 37.3 mmol) in 75 mL of CH₂Cl₂ was treated with 75 mL ofconcentrated NH₄OH solution. The mixture was chilled in an ice waterbath. To the rapidly stirred mixture was added solid p-toluenesulfonylchloride (7.82 g, 41.0 mmol) over a 10 min period. The reaction mixturewas then warmed to room temperature. After 30 min, the reaction wastreated with 75 mL of CH₂Cl₂ and 75 mL of water and the layers wereseparated. The organic portion was then washed with 1% Na₂CO₃ solution(2×), water, brine, dried over Na₂SO₄ and concentrated give 14.95 g oftert-butyl2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow solid.

[0406] Part D

[0407] Tert-butyl2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(14.45 g, 33.6 mmol) was dissolved in 50 mL of 2M HCl in EtOH and themixture was heated to reflux with stirring. After 3 h, the reaction wascooled to room temperature and treated with ether (100 mL). The HCl saltof the product was collected by vacuum filtration The free base was madeby dissolving the hydrochloride salt in 75 mL of water and treating withconcentrated NH₄OH until pH 12 was reached. The aqueous suspension wasextracted with CH₂Cl₂ (4×50 mL). The combined organic layers were driedover Na₂SO₄ and concentrated to give a thick orange oil. The oil wasdissolved in MeOH (100 mL), treated with 2 g of activated charcoal andheated to reflux. After 2 h, the mixture was filtered through a pad ofCelite and rinsed with portions of MeOH. The filtrate was concentratedto yield1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a sticky orange solid.

[0408] MS 330 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (d, J=8.1 Hz,1H), 7.62 (d, J=7.5 Hz, 1H), 7.44 (m, 1H), 7.25 (m, 1H), 6.58 (s, 2H),4.85 (t, J=5.5 Hz, 2H), 4.80 (s, 2H), 3.86 (t, J=5.5 Hz, 2H), 3.56 (q,J=7.0 Hz, 2H), 3.30 (t, J=5.5 Hz, 2H), 2.54 (t,J=5.6 Hz, 2H), 1.17 (t,J=7.0 Hz, 3H).

EXAMPLE 48N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea

[0409]

[0410] A solution of the compound of Example 45,1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine(1.411 g, 4.95 mmol) in 40 mL of 1-methyl-2-pyrrolidinone was treatedwith triethylamine (1.38 mL, 9.89 mmol). With vigorous stirring, thesolution was treated with phenyl isocyanate (0.538, 4.95 mmol). After 18h, the reaction was concentrated to yield an off white solid.Purification by column chromatography (SiO₂, 9:1 CH₂Cl₂:MeOH) gave 351mg ofN-{2-[2-(4-amino-2-methyl-1H-midazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylureaas a white powder.

[0411] mp=193-195° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.06(d, J=7.6, 1H), 7.62 (dd, J=1.0, 8.3 Hz, 1H), 7.44-7.35 (m, 3H),7.26-7.18 (m, 3H), 6.88 (t, J=7.3 Hz, 1H), 6.59 (s, 2H), 6.12 (t, J=5.6Hz, 1H), 4.72 (t, J=5.2 Hz, 2H), 3.89 (t, J=5.1 Hz, 2H), 3.40 (t, J=5.7Hz, 2H), 3.21-3.15 (m, 2H), 2.62 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ155.5, 151.9, 151.1, 144.6, 140.8, 132.9, 129.0, 126.7, 126.5, 126.3,121.5, 121.4, 120.4, 118.0, 115.0, 70.5, 69.3, 45.8, 39.1, 14.1; MS n/z405 (M+H)⁺; Anal. Calcd for C₂₂H₂₄N₆O₂.0.15H₂O: C, 64.89, H, 6.02, N,20.64. Found: C, 64.55, H, 5.72, N, 20.50.

EXAMPLE 49N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N-cyclohexylurea

[0412]

[0413] A solution of the compound of Example 45,1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-midazo[4,5-c]quinolin-4-amine(1.00 g, 3.50 mmol) in 30 mL of pyridine was chilled in an ice waterbath. With vigorous stirring, the solution was treated with cyclohexylisocyanate (0.45 mL, 3.50 mmol). After 18 h, the reaction wasconcentrated to yield an off white solid. Purification by columnchromatography (SiO₂, 95:5:0.5 CHCl₃:MeOH:NH₄OH) gave 716 mg ofN-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexylureaas a white solid.

[0414] mp=207-209° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (d, J=7.5 Hz,1H), 7.60 (dd, J=1.0, 8.3 Hz, 1H), 7.41 (m, 1H), 7.23 (m, 1H), 6.47 (s,2H), 5.77 (d, J=8.0 Hz, 1H), 5.65 (t, J=5.7 Hz, 1H), 4.68 (t, J=5.2 Hz,2H), 3.85 (t, J=5.2 Hz, 2H), 3.32 (t, J=5.6 Hz, 2H), 3.07 (t, J=5.6 Hz,2H), 2.60 (s, 3H), 1.76-1.56 (m, 4H), 1.56-1.45 (m, 1H), 1.31-0.96 (m,6H); ¹³C NMR (75 MHz, DMSO-d₆) δ 157.5, 152.0, 151.0, 145.0, 132.8,126.6, 121.4, 120.4, 115.1, 70.8, 69.2, 48.0, 45.8, 33.6, 25.7, 24.8,14.1; MS m/z 411 (M+H)⁺; Anal. Calcd for C₂₂H₃₀N₆O₂: C, 64.37; H, 7.37;N, 20.47; Found: C, 64.08; H, 7.30; N, 20.34.

EXAMPLE 50N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea

[0415]

[0416] A solution of the compound of Example 46,1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine(800 mg, 2.67 mmol) in 30 mL of CH₂Cl₂ was stirred vigorously andtreated with phenyl isocyanate (0.290 mL, 2.67 mmol). After 18 h, thereaction was concentrated to yield an off white solid. Purification bycolumn chromatography (SiO₂, 95:5:0.5 CHCl₃:MeOH:NH₄OH) gave 559 mg ofN-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylureaas a white solid.

[0417] mp=141-144° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.05(d, J=7.4 Hz, 1H), 7.62 (dd, J=1.1, 8.3 Hz, 1H), 7.43-7.33 (m, 3H),7.28-7.17 (m 3H), 6.92-6.85 (m, 1H), 6.44 (s, 2H), 6.10 (t, J=5.6 Hz,1H), 4.73 (t, J=5.2 Hz, 2H), 3.89 (t, J=5.2 Hz, 2H), 3.40 (t, J=5.7 Hz,2H), 3.18 (t, J=5.5 Hz, 2H), 2.97 (q, J=7.5 Hz, 2H), 1.35 (t, J=7.5 Hz,3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 155.5, 155.2, 152.0, 145.1, 140.8,132.8, 129.0, 126.7, 121.4, 120.4, 118.0, 115.2, 70.5, 69.3, 45.4, 20.3,12.2; MS m/z 419(M+H)⁺; Anal. Calcd for C₂₃H₂₆N₆O₂.0.88H₂O: C, 63.61; H,6.44; N, 19.35; Found: C, 63.88; H, 6.36; N, 19.47; KF=3.64% H₂O.

EXAMPLE 51N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexylurea

[0418]

[0419] A solution of the compound of Example 46,1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine(800 mg, 2.67 mmol) in 30 mL of pyridine was chilled in an ice waterbath. With vigorous stirring, the solution was treated with cyclohexylisocyanate (0.340 mL, 2.67 mmol). After 1 h, the reaction wasconcentrated to yield an off white solid. Purification by columnchromatography (SiO₂, 95:5:0.5 CHCl₃:MeOH:NH₄OH) gave 748 mg ofN-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexylureaas a white solid.

[0420] mp=198-200° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (d, J=7.7 Hz,1H), 7.63 (dd, J=1.1, 8.3 Hz, 1H), 7.40 (m, 1H), 7.24 (m, 1H), 6.46 (s,2H), 5.78 (d, J=7.9 Hz, 1H), 5.65 (t, J=5.6 Hz, 1H), 4.60 (t, J=5.3 Hz,2H), 3.85 (t, J=5.2 Hz, 2H), 3.31 (t, J=5.6 Hz, 2H), 3.06 (q, J=5.3 Hz,2H), 2.97 (q, J=7.4 Hz, 2H), 1.76-1.56 (m, 4H), 1.56-1.45 (m, 1H), 1.38(t, J=7.4 Hz, 3H), 1.30-0.97 (m, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ 157.5,155.2, 152.0, 145.1, 132.8, 126.7, 126.6, 121.4, 120.4, 115.2, 70.8,69.2, 48.1, 45.3, 39.2, 33.6, 25.7, 24.8, 20.3, 12.2; MS m/z 425 (M+H)⁺;Anal. Calcd for C₂₃H₃₂N₆O₂: C, 65.07; H, 7.60; N, 19.80; Found: C,64.87; H, 7.52; N, 19.82.

EXAMPLE 52N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}morpholine-4-carboxamide

[0421]

[0422] A solution of the compound of Example 46,1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine(800 mg, 2.67 mmol) in 30 mL of pyridine was chilled in an ice waterbath. With vigorous stirring, the solution was treated with4-morpholinecarbonyl chloride (0.310 mL, 2.67 mmol). After 1 h, thereaction was concentrated to yield an off white solid. Purification bycolumn chromatography (SiO₂, 95:5:0.5 CHCl₃:MeOH:NH₄OH) followed bytrituration in ether gave 563 mg ofN-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}morpholine-4-carboxamideas a white solid.

[0423] mp=182-184° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (d, J=7.5 Hz,1H), 7.62 (dd, J=1.1, 8.3 Hz, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 6.43 (s,2H), 6.12 (t, J=5.4 Hz, 1H), 4.69 (t, J=5.2 Hz, 2H), 3.86 (t, J=5.3 Hz,2H), 3.50 (t, J=5.0 Hz, 4H), 3.36-3.30 (m, 2H), 3.15 (t,J=5.0 Hz, 4H),3.08 (q,J=5.7 Hz, 2H), 2.96 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H);¹³C NMR (75 MHz, DMSO-d₆) δ 157.8, 155.2, 152.0, 145.1, 132.8, 126.7,126.6, 121.3, 120.3, 115.2, 70.2, 69.2, 66.2, 45.4, 44.0, 20.3, 12.2; MSm/z 413 (M+H)⁺; Anal. Calcd for C₂₁H₂₈N₆O₃.0.07 CHCl₃: C, 60.21; H,6.73; N, 20.00; Found: C, 60.25; H, 6.62; N, 19.99.

EXAMPLE 53N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea

[0424]

[0425] A solution of the compound of Example 47,1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(980 mg, 2.98 mmol) in 20 mL of CH₂Cl₂ was chilled in an ice water bath.With vigorous stirring, the solution was treated with phenyl isocyanate(0.340 mL, 3.13 mmol). After 30 min, the reaction was concentrated toyield a yellow foam. Purification by column chromatography (SiO₂,95:5:0.5 CHCl₃:MeOH:NH₄OH) followed by recrystallization fromMeOH/CHCl₃/hexanes gave 529 mg ofN-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylureaas light yellow crystals.

[0426] mp=183-186° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.09(d, J=6.6 Hz, 1H), 7.62 (dd, J=1.1, 8.3 Hz, 1H), 7.47-7.35 (m, 3H),7.29-7.18 (m, 3H), 6.89 (m, 1H), 6.63 (s, 2H), 6.14 (t, J=4.7 Hz, 1H),4.83 (t, J=5.5 Hz, 2H), 4.80 (s, 2H), 3.91 (t, J=5.5 Hz, 2H), 3.53 (q,J=7.0 Hz, 2H), 3.43 (t, J=5.7 Hz, 2H), 3.20 (q, J=5.4 Hz, 2H), 1.14 (t,J=7.0 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 155.5, 152.3, 149.9, 145.5,140.8, 133.5, 129.0, 126.7, 121.5, 121.4, 120.8, 118.0, 115.0, 70.5,69.2, 65.7, 64.7, 39.1, 15.3; MS m/Z 449 (M+H)⁺; Anal. Calcd forC₂₄H₂₈N₆O₃: C, 64.27; H, 6.29; N, 18.74; Found: C, 63.92; H, 6.28; N,18.38.

EXAMPLE 54N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-cyclohexylurea

[0427]

[0428] A solution of the compound of Example 47,1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(980 mg, 2.98 mmol) in 20 mL of CH₂Cl₂ was chilled in an ice water bath.With vigorous stirring, the solution was treated with cyclohexylisocyanate (0.400 mL, 3.13 mmol). After 30 min, the reaction wasconcentrated to yield a yellow foam. Purification by columnchromatography (SiO₂, 95:5:0.5 CHCl₃:MeOH:NH₄OH) followed byrecrystallization from acetonitrile gave 400 mg ofN-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-cyclohexylureaas an off white solid.

[0429] mp=161-164° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=8.0 Hz,1H), 7.63 (d, J=7.5 Hz, 1H), 7.45 (t, J=7.2 Hz, 1H), 7.25 (t, J=7.1 Hz,1H), 6.60 (s, 2H), 5.77 (d, J=8.0 Hz, 1H), 5.68 (t, J=5.6 Hz, 1H),4.86-4.75 (m, 4H), 3.87 (t, J=5.6 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H),3.40-3.28 (m, 2H), 3.06 (q, J=5.5 Hz, 2H), 1.77-1.45 (m, 5H), 1.40-1.00(m, 6H), 1.16 (t, J=7.0 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 157.5,152.3, 149.9, 145.5, 133.5, 127.2, 126.7, 121.5, 120.8, 115.0, 70.9,69.2, 65.7, 64.7, 48.1, 45.6, 33.6, 25.7, 24.8, 15.3; MS m/z 455 (M+H)⁺;Anal. Calcd for C₂₄H₃₄N₆O₃: C, 63.41; H, 7.54; N, 18.49; Found: C,63.30; H, 7.46; N, 18.37.

EXAMPLE 55N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide

[0430]

[0431] A solution of the compound of Example 47,1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(980 mg, 2.98 mmol) in 20 mL of CH₂Cl₂ was treated with triethylamine(1.04 mL, 7.45 mmol) and chilled in an ice water bath. With vigorousstirring, the solution was treated with 4-morpholinecarbonyl chloride(0.365 mL, 3.13 mmol). After 18 h, the reaction was treated with 25 mLCH₂Cl₂ and 25 mL water and the layers were separated. The organicportion was washed with 1% Na₂CO₃ solution, water and brine. The organicportion was then dried over Na₂SO₄, filtered and concentrated to yield ayellow foam. Purification by column chromatography (SiO₂, 95:5:0.5CHCl₃:MeOH:NH₄OH) gave 393 mg ofN-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide as a yellow solid.

[0432] mp=178-181° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.20 (dd, J=1.0, 8.3Hz, 1H), 7.81 (dd, J=1.0, 8.4 Hz, 1H), 7.52 (m, 1H), 7.30 (m, 1H), 5.41(s, 2H), 4.85 (t, J=5.1 Hz, 2H), 4.83 (s, 2H), 4.20 (t, J=5.2 Hz, 1H),3.96 (t, J=5.1 Hz, 2H), 3.62 (q, J=7.0 Hz, 2H), 3.51 (t, J=5.0 Hz, 4H),3.42 (t, J=5.0 Hz, 2H), 3.30 (q, J=5.2 Hz, 2H), 2.87 (t, J=5.0 Hz, 4H),1.25 (t, J=7.0 Hz, 3H); ³C NMR (75 MHz, CDCl₃) δ 157.3, 151.3, 149.7,145.1, 127.7, 127.3, 122.1, 120.5, 115.5, 70.8, 70.0, 66.5, 66.3, 65.3,46.0, 43.5, 40.3, 15.1; MS m/z 443 (M+H)⁺; Anal. Calcd for C₂₂H₃₀N₆O₄:C, 59.71; H, 6.83; N, 18.99; Found: C, 59.63; H, 6.81; N, 18.81.

Cytokine Induction In Human Cells

[0433] An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon and tumornecrosis factor (α) (IFN and TNF, respectively) secreted into culturemedia as described by Testerman et. al. In “Cytokine Induction by theImmunomodulators Imiquimod and S-27609”, Journal of Leukocyte Biology,58, 365-372 (September, 1995).

[0434] Blood Cell Preparation for Culture

[0435] Whole blood from healthy human donors is collected byvenipuncture into EDTA vacutainer tubes. Peripheral blood mononuclearcells (PBMC) are separated from whole blood by density gradientcentrifugation using Histopaque®-1077. Blood is diluted 1:1 withDulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced SaltsSolution (HBSS). The PBMC layer is collected and washed twice with DPBSor HBSS and resuspended at 4×10⁶ cells/mL in RPMI complete. The PBMCsuspension is added to 48 well flat bottom sterile tissue culture plates(Costar, Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park,N.J.) containing an equal volume of RPMI complete media containing testcompound.

[0436] Compound Preparation

[0437] The compounds are solubilized in dimethyl sulfoxide (DMSO). TheDMSO concentration should not exceed a final concentration of 1% foraddition to the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM.

[0438] Incubation

[0439] The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(30-0.014 μM). The final concentration of PBMC suspension is 2×10⁶cells/mL. The plates are covered with sterile plastic lids, mixed gentlyand then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxideatmosphere.

[0440] Separation

[0441] Following incubation the plates are centrifuged for 10 minutes at1000 rpm (˜200×g) at 4° C. The cell-free culture supernatant is removedwith a sterile polypropylene pipet and transferred to sterilepolypropylene tubes. Samples are maintained at −30 to −70° C. untilanalysis. The samples are analyzed for interferon (α) by ELISA and fortumor necrosis factor (α) by ELISA or IGEN Assay

[0442] Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

[0443] Interferon (α) concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.Results are expressed in pg/mL.

[0444] Tumor necrosis factor (α) (TNF) concentration is determined usingELISA kits available from Biosource International, Camarillo, Calif.Alternately, the TNF concentration can be determined by Origen® M-SeriesImmunoassay and read on an IGEN M-8 analyzer from IGEN International,Gaithersburg, Md. The immunoassay uses a human TNF capture and detectionantibody pair from Biosource International, Camarillo, Calif. Resultsare expressed in pg/mL.

[0445] The table below lists the lowest concentration found to induceinterferon and the lowest concentration found to induce tumor necrosisfactor for each compound. A “*” indicates that no induction was seen atany of the tested concentrations; generally the highest concentrationtested was 10 or 30 μM. Cytokine Induction in Human Cells Example LowestEffective Concentration (μM) Number Interferon Tumor Necrosis Factor 30.01 0.37 7 0.0001 10 8 0.0001 10 9 0.0001 1 10 0.0001 10 11 0.0001 0.112 0.0001 1 13 0.0001 1 14 0.0001 10 15 0.0001 0.1 16 0.0001 10 17 * 1018 1 * 19 0.1 10 20 0.01 10 21 1 10 22 0.1 1 23 1 1 24 0.1 1 25 0.1 1 260.1 1 27 0.1 1 28 0.1 1 29 0.1 1 30 1 1 31 1 10 32 0.1 1 33 1 10 34 1 1035 1 1 36 0.1 * 37 10 10 38 10 10 39 10 10 40 10 10 41 10 10 42 10 * 4310 10 44 * *

What is claimed is:
 1. A compound of the Formula (I):

wherein: X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-; R₁ is selectedfrom the group consisting of: R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl;R₄—NR₈—CR₃—NR₅-Z-R₆-alkenyl; R₄—NR₈—CR₃—NR₅-Z-R₆-aryl;R₄—NR₈—CR₃—NR₅-Z-R₆-heteroaryl; R₄—NR₈—CR₃—NR₅-Z-R₆-heterocyclyl;R₄—NR₈—CR₃—NR₅R₇; R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl; R₄—NR₈—CR₃—NR₉-Z-R₆alkenyl;R₄—NR₈—CR₃—NR₉-Z-R₆-aryl; R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; andR₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl; R₂ is selected from the groupconsisting of: hydrogen; alkyl; alkenyl; aryl; heteroaryl; heterocyclyl;alkyl-Y-alkyl; alkyl-Y-alkenyl; alkyl-Y-aryl; and alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: OH; halogen; N(R₅)₂; CO—N(R₅)₂; CO—C₁₋₁₀ alkyl;CO—O—C₁₋₁₀ alkyl; N₃; aryl; heteroaryl; heterocyclyl; CO-aryl; andCO-heteroaryl; R₃ is ═O or ═S; R₄ is alkyl or alkenyl, which may beinterrupted by one or more —O— groups; each R₅ is independently H orC₁₋₁₀ alkyl; R₆ is a bond, alkyl, or alkenyl, which may be interruptedby one or more —O— groups; R₇ is H or C₁₋₁₀ alkyl which may beinterrupted by a hetero atom, or R₇ can join with R₅ to form a ring; R₈is H, C₁₋₁₀ alkyl, or arylalkyl; or R₄ and R₈ can join together to forma ring; R₉ is C₁₋₁₀ alkyl which can join together with R₈ to form aring; Y is —O— or —S(O)₀₋₂—; Z is a bond, —CO—, or —SO₂—; n is 0 to 4;and each R present is independently selected from the group consistingof C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 2. A compound or salt of claim1 wherein X is —CH(alkyl)-alkyl-, wherein the alkyl groups can be thesame or different.
 3. A compound or salt of claim 1 wherein X is—CH₂—CH₂—.
 4. A compound or salt of claim 1 wherein X is —CH(C₂H₅)—CH₂—.5. A compound or salt of claim 1 wherein R₂ is H.
 6. A compound or saltof claim 1 wherein R₂ is alkyl.
 7. A compound or salt of claim 1 whereinR₂ is -alkyl-O-alkyl.
 8. A compound or salt of claim 1 wherein n is o.9. A compound selected from the group consisting of:N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea;N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea;N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide;N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmorpholine-4-carboxamide;N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N′-phenylurea;andN-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N′-phenylurea; or a pharmaceutically acceptable saltthereof.
 10. A compound selected from the group consisting of:N-{2-[2-(4-amino-2-methyl-1H imidazo[4, 5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexyl urea; N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl) ethoxy]ethyl}-N′-phenylurea;N-{2-[2-(4-amino-2-ethyl-1H imidazo[4, 5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexyl urea;N-{2-[2-(4-amino-2-methyl-1H-imidazo[4, 5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea; and N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl) ethoxy] ethyl} morpholine-4-carboxamide;N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea;N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-cyclohexylurea;N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 11. A compound of theformula (II)

wherein: X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-; R₁ is selectedfrom the group consisting of: R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl;R₄—NR₈—CR₃—NR₅-Z-R₆-alkenyl; R₄—NR₈—CR₃—NR₅-Z-R₆-aryl;R₄-NR₈—CR₃—NR₅-Z-R₆-heteroaryl; R₄—NR₈—CR₃—NR₅-Z-R₆-heterocyclyl;R₄—NR₈—CR₃—NR₅R₇; R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl;R₄—NR₈—CR₃—NR₉-Z-R₆-alkenyl; R₄—NR₈—CR₃—NR₉-Z-R₆-aryl;R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; and R₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl; R₂is selected from the group consisting of: hydrogen; alkyl; alkenyl;aryl; heteroaryl; heterocyclyl; alkyl-Y-alkyl; alkyl-Y-alkenyl;alkyl-Y-aryl; and alkyl or alkenyl substituted by one or moresubstituents selected from the group consisting of: OH; halogen; N(R₅)₂;CO—N(R₅)₂; CO—C₁₋₁₀ alkyl; CO—O—C₁₋₁₀ alkyl; N₃; aryl; heteroaryl;heterocyclyl; CO-aryl; and CO-heteroaryl; R₃ is ═O or ═S; R₄ is alkyl oralkenyl, which may be interrupted by one or more —O— groups; each R₅ isindependently H or C₁₋₁₀ alkyl; R₆ is a bond, alkyl, or alkenyl, whichmay be interrupted by one or more —O— groups; R₇ is H or C₁₋₁₀ alkylwhich may be interrupted by a hetero atom, or R₇ can join with R₅ toform a ring; R₈ is H, C₁₋₁₀ alkyl, or arylalkyl; or R₄ and R₈ can jointogether to form a ring; R₉ is C₁₋₁₀ alkyl which can join together withR₈ to form a ring; Y is —O— or —S(O)₀₋₂—; Z is a bond, —CO—, or —SO₂—; nis 0 to 4; and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen, andtrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 12. Acompound or salt of claim 11 wherein R₂ is H or alkyl.
 13. A compound orsalt of claim 11 wherein R₂ is -alkyl-O-alkyl.
 14. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor salt of claim 1 and a pharmaceutically acceptable carrier.
 15. Amethod of inducing cytokine biosynthesis in an animal comprisingadministering a therapeutically effective amount of a compound or saltof claim 1 to the animal.
 16. The method of claim 15 wherein thecytokine is IFN-α.
 17. A method of treating a viral disease in an animalcomprising administering a therapeutically effective amount of acompound or salt of claim 1 to the animal.
 18. A method of treating aneoplastic disease in an animal comprising administering atherapeutically effective amount of a compound or salt of claim 1 to theanimal.
 19. A compound of the formula (III):

wherein: X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-; R₁ is selectedfrom the group consisting of: R₄—NR₈—R₃—NR₅-Z-R₆-alkyl;R₄—NR₈—CR₃—NR₅-Z-R₆-alkenyl; R₄—NR₈—CR₃—NR₅-Z-R₆-aryl;R₄—NR₈—CR₃—NR₅-Z-R₆-heteroaryl; R₄—NR₈—CR₃—NR₅-Z-R₆-heterocyclyl;R₄—NR₈—CR₃—NR₅R₇; R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl;R₄—NR₈—CR₃—NR₉-Z-R₆-alkenyl; R₄—NR₈—CR₃—NR₉-Z-R₆-aryl;R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; and R₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl; R₂is selected from the group consisting of: hydrogen; alkyl; alkenyl;aryl; heteroaryl; heterocyclyl; alkyl-Y-alkyl; alkyl-Y-alkenyl;alkyl-Y-aryl; and alkyl or alkenyl substituted by one or moresubstituents selected from the group consisting of: OH; halogen; N(R₅)₂;CO—N(R₅)₂; CO—C₁₋₁₀ alkyl; CO—O—C₁₋₁₀ alkyl; N₃; aryl; heteroaryl;heterocyclyl; CO-aryl; and CO-heteroaryl; R₃ is ═O or ═S; R₄ is alkyl oralkenyl, which may be interrupted by one or more —O— groups; each R₅ isindependently H or C₁₋₁₀ alkyl; R₆ is a bond, or is alkyl, or alkenyl,which may be interrupted by one or more —O— groups; R₇ is H or C₁₋₁₀alkyl which may be interrupted by a hetero atom, or R₇ can join with R₅to form a ring; R₈ is H, C₁₋₁₀ alkyl, arylalkyl; or R₄ and R₈ can jointo form a ring; R₉ is C₁₋₁₀ alkyl which can join together with R₈ toform a ring; Y is —O— or —S(O)₀₋₂—; Z is a bond, —CO—, or —SO₂—; n is 0to 4; and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 20. Acompound of the formula (IV):

wherein: X is —CHR₅—, —CHR₅-alkylene-, or —CHR₅-alkenylene-; R₁ isselected from the group consisting of: R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl;R₄—NR₈—CR₃—NR₅-Z-R₆-alkyl; R₄—NR₈—CR₃—NR₅-Z-R₆-aryl;R₄—NR₈—CR₃—NR₅-Z-R₆-heteroaryl; R₄—NR₈—C R₃—NR₅-Z-R₆-heterocyclyl;R₄—NR₈—CR₃—NR₅R₇; R₄—NR₈—CR₃—NR₉-Z-R₆-alkyl;R₄—NR₈—CR₃—NR₉-Z-R₆-alkenyl; R₄—NR₈—CR₃—NR₉Z-R₆-aryl;R₄—NR₈—CR₃—NR₉-Z-R₆-heteroaryl; and R₄—NR₈—CR₃—NR₉-Z-R₆-heterocyclyl; Zis a bond, —CO—, or —SO₂—; R₃ is ═O or ═S; R₄ is alkyl or alkenyl, whichmay be interrupted by one or more —O— groups; each R₅ is independently Hor C₁₋₁₀ alkyl; R₆ is a bond, or is alkyl, or alkenyl, which may beinterrupted by one or more —O— groups; R₇ is H or C₁₋₁₀ alkyl which maybe interrupted by a hetero atom, or R₇ can join with R₅ to form a ring;R₈ is H, C₁₋₁₀ alkyl, or arylalkyl; or R₄ and R₈ can join to form aring; R₉ is C₁₋₁₀ alkyl which can join together with R₈ to form a ring;n is 0 to 4; and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl; ora pharmaceutically acceptable salt thereof.
 21. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor salt of claim 11 and a pharmaceutically acceptable carrier.
 22. Amethod of inducing cytokine biosynthesis in an animal comprisingadministering a therapeutically effective amount of a compound or saltof claim 11 to the animal.
 23. The method of claim 22 wherein thecytokine is IFN-α.
 24. A method of treating a viral disease in an animalcomprising administering a therapeutically effective amount of acompound or salt of claim 11 to the animal.
 25. A method of treating aneoplastic disease in an animal comprising administering atherapeutically effective amount of a compound or salt of claim 11 tothe animal.